Combination composition comprising oxycodone and acetaminophen for rapid onset and extended duration of analgesia

ABSTRACT

The present disclosure provides an extended release pharmaceutical composition comprising oxycodone and acetaminophen that provides a rapid onset of analgesia, and reduced levels of acetaminophen near the end of the dosing interval. Also provided are methods for reducing the risk of acetaminophen-induced hepatic damage in a subject being treated with an acetaminophen containing composition, as well as methods for treating pain in a subject in need thereof.

RELATED CASES

This application claims priority to U.S. Provisional Application No.61/487,047 filed on May 17, 2011, U.S. Provisional Application No.61/537,527 filed on Sep. 21, 2011, and U.S. Provisional Application No.61/606,850 filed on Mar. 5, 2012 which are incorporated herein byreference in their entirety to the full extent permitted by law.

FIELD OF THE INVENTION

The present disclosure relates to an extended release pharmaceuticalcomposition comprising oxycodone and acetaminophen that provides a rapidonset of analgesia, followed by an extended duration of analgesia ofabout 12 hours.

BACKGROUND OF THE INVENTION

Oral drug administration remains the route of choice for the majority ofclinical applications. Modified release (MR) dosage forms that areadministered once or twice daily offer advantages over their immediaterelease (IR) counterparts because they reduce the magnitude of peaks andtroughs of drug plasma concentration, provide longer dosing intervals,sustained analgesic effect, and increased patient compliance. Thesemodified release formulations may be referred to as controlled release(CR), sustained release (SR) and/or extended release (ER) etc. Forcertain types of patients, such as those suffering from pain, these MRproducts may permit the patient to sleep through the night withouthaving to wake up during the night to take the next dose. Thus, it cansignificantly increase the quality of life for such patients. Both IRand MR products for pain are widely available in the market. Examples ofIR products include those containing NSAIDs, opioids, profens, COX IIinhibitors and aspirin (Tylenol, Advil, Celebrex, Vioxx, Aleve,Voltaren). Examples of MR products include those containing NSAIDs andopioids (Tylenol SR, Oxycontin).

Researchers have also combined various classes of pain drugs to providebetter analgesia to patients. For example, a combination ofacetaminophen-oxycodone hydrochloride is commercially available asPercocet and acetaminophen-hydrocodone bitartrate as Vicodin. Inrandomized controlled trials, it was shown that the combination productPercocet was statistically superior to MR oxycodone in various outcomemeasures of pain relief. Other combination products such asAcetaminophen-Hydrocodone and Acetaminophen-Tramadol are eitheravailable or described in the literature. It is postulated that thecombination of two analgesic drugs with complementary mechanisms ofaction results in enhanced analgesia due to an additive effect, an“opioid-sparing” effect, and an improved side effect and safety profile.The improved safety profile results from the use of reduced doses of twoanalgesics with different side-effects rather than an equieffective doseof a single agent.

Acetaminophen is absorbed from the small intestine and primarilymetabolized by conjugation, like glucuronidation and sulfation, in theliver to nontoxic, water-soluble compounds that are eliminated in theurine. When the maximum daily dose is exceeded over a prolonged period,metabolism by conjugation becomes saturated, and excess acetaminophen isoxidatively metabolized by cytochrome P450 (CYP) enzymes (e.g., CYP2E1,1A2, 2A6, 3A4) to a reactive metabolite, N-acetyl-p-benzoquinone-imine(NAPQI). NAPQI is a reactive free radical with an extremely shorthalf-life that is rapidly inactivated by conjugation with glutathione,which is acting as a sulfhydryl donor. Once the pool of availableglutathione is exhausted, the cysteines of cellular proteins becomesulfhydryl donors to NAPQI, binding covalently and initiating a cascadeof oxidative and cellular damage, resulting in necrosis and, ultimately,liver failure. Thus, avoiding excessive NAPQI formation is an importantstrategy when using acetaminophen, although to dateacetaminophen-sparing has not been an approach any manufacturers havechosen to take. However, due to the prevalence of acetaminophen in manyover-the-counter products, it is prudent to consideracetaminophen-sparing precautions when considering combination therapylasting more than a few days to avoid an inadvertent reduction inglutathione stores.

Thus, various options for pain management are available that are both IRand MR, and contain either a single drug or a combination of analgesics.While these combination products provide the benefits associated withcombining two analgesics as described above, both IR and MR, in itself,have a significant disadvantage. IR combination products lack theadvantages of MR products described previously. MR combination productslack a significant benefit associated with IR products—rapid onset ofanalgesia—that is extremely desirable for pain management. Because MRproducts retard the rate of drug release to sustain the drug effect overprolonged period, release of drug is slow resulting in significant timebefore effective analgesic drug concentration is attained in thebloodstream. There exists a clinical need for pain management thatcombines the desirable features of IR and MR in combination painproducts.

SUMMARY OF THE INVENTION

Among the various aspects of the present disclosure is a pharmaceuticalcomposition for extended release of oxycodone and acetaminophencomprising at least one extended release portion comprising oxycodone,acetaminophen or a combination thereof, and at least one extendedrelease component. The composition, when orally administered to asubject, maintains a therapeutic plasma concentration of oxycodone of atleast about 5 ng/mL from about 0.75 hour to about 10 hours afteradministration of the composition. Additionally, at least about 90% ofthe acetaminophen is released from the composition by about 8 hoursafter administration of the composition such that, by about 10 hoursafter administration of the composition, acetaminophen has a bloodplasma concentration that is less than about 30% of acetaminophen'smaximum plasma concentration.

A further aspect of the disclosure encompasses a pharmaceuticalcomposition for extended release of oxycodone and acetaminophencomprising (a) at least one immediate release portion comprisingoxycodone, acetaminophen or a combination thereof, and (b) at least oneextended release portion comprising oxycodone, acetaminophen or acombination thereof, and an extended release component, wherein about30% of the oxycodone in the pharmaceutical composition is released inabout 15 minutes and at least about 90% of the acetaminophen in thepharmaceutical composition is released in about 8 hours when measured in900 ml of 0.1N HCl using a USP type II apparatus at a paddle speed ofabout 100 rpm and a constant temperature of 37° C.

Yet another aspect of the disclosure provides a pharmaceuticalcomposition for oral administration in the treatment of pain, comprising(a) at least one immediate release portion comprising acetaminophen andoxycodone or a pharmaceutically acceptable salt thereof; and (b) atleast one extended release portion comprising acetaminophen andoxycodone or salt thereof, and an extended release component, whereinthe total amount of acetaminophen in the composition is about 325 mg toabout 650 mg, and the total amount of oxycodone or salt in thecomposition is about 7.5 mg to about 15 mg, and wherein upon placementof the composition in an in vitro dissolution test comprising USP PaddleMethod at a paddle speed of about 100 rpm in 900 ml of 0.1N HCl using aUSP type II apparatus at a constant temperature of 37° C., about 30%, byweight, of the oxycodone or salt thereof is released at about 15 minutesin the test and at least about 90%, by weight, of the acetaminophen isreleased at about 8 hours in the test. Further, upon oral administrationof a single dose of the composition to a subject in need of analgesia,the composition provides a C_(max) for oxycodone from about 0.9 ng/mL/mgto about 1.6 ng/mL/mg, a C_(max) for acetaminophen from about 4.0ng/mL/mg to about 11.0 ng/mL/mg, a T_(max) for oxycodone from about 2hours to about 7 hours, and a T_(max) for acetaminophen from about 0.5hour to about 6 hours.

In a further aspect of the disclosure provides a pharmaceuticalcomposition for oral administration in the treatment of pain, comprising(a) at least one immediate release portion comprising acetaminophen andoxycodone or a pharmaceutically acceptable salt thereof, and (b) atleast one extended release portion comprising acetaminophen andoxycodone or salt thereof, and an extended release component; whereinthe total amount of acetaminophen in the composition is about 325 mg toabout 650 mg, and the total amount of oxycodone or salt in thecomposition is about 7.5 mg to about 15 mg. Moreover, upon placement ofthe composition in an in vitro dissolution test comprising USP PaddleMethod at a paddle speed of about 150 rpm in 900 ml of 0.1N HCl using aUSP type II apparatus at a constant temperature of 37° C., no more thanabout 65%, by weight, of the total amount of the oxycodone or salt isreleased and no more than about 75%, by weight, of the total amount ofthe acetaminophen is released after 2 hours; from about 65% to about85%, by weight, of the total amount of the oxycodone or salt is releasedand from about 70% to about 90%, by weight, of the total amount of theacetaminophen is released after 4 hours; from about 85% to about 100%,by weight, of the total amount of the oxycodone or salt is released andfrom about 85% to about 100%, by weight, of the total amount of theacetaminophen is released after 8 hours; and from about 95% to about100%, by weight, of the total amount of the oxycodone or salt isreleased and from about 90% to about 100%, by weight, of the totalamount of the acetaminophen is released after 12 hours.

An additional aspect of the disclosure provides for a pharmaceuticalcomposition for oral administration in the treatment of pain, comprising(a) at least one immediate release portion comprising acetaminophen andoxycodone or a pharmaceutically acceptable salt thereof; and (b) atleast one extended release portion comprising acetaminophen andoxycodone or salt thereof, and an extended release component; whereinthe total amount of acetaminophen in the composition is about 325 mg toabout 650 mg, and the total amount of oxycodone or salt in thecomposition is about 7.5 mg to about 15 mg. And upon oral administrationof the composition in an amount of about 15 mg oxycodone or salt andabout 650 mg acetaminophen, the composition provides an AUC_(0-1.7h) foracetaminophen of about 5.0 ng·h/mL/mg to about 13.0 ng·h/ml/mg; anAUC_(1.7-48h) for acetaminophen of about 25.0 ng·h/mL/mg to about 75.0ng·h/mL/mg; an AUC_(0-2.8h) for oxycodone or salt of about 1.0ng·h/mL/mg to about 3.0 ng·h/mL/mg; and AUC_(2.8-48h) of about 7.5ng·h/mL/mg to about 15.0 ng·h/mL/mg.

Still another aspect of the disclosure provides a dosage form comprising(a) an immediate release portion comprising acetaminophen and oxycodone,wherein the immediate release portion comprises, by weight of theimmediate release portion, from about 70% to about 80% of acetaminophenand from about 0.5% to about 1% of oxycodone; and (b) an extendedrelease portion comprising acetaminophen, oxycodone, and an extendedrelease polymer, wherein the extended release portion comprises, byweight of the extended release portion, from about 20% to about 40% ofacetaminophen, from about 0.5% to about 2% of oxycodone, and from about30% to about 50% of the extended release polymer.

Another aspect provides a dosage form comprising from about 7.5 mg toabout 30 mg of oxycodone and from about 325 mg to about 650 mg ofacetaminophen. The dosage form comprises (a) at least one immediaterelease portion comprising about 25% of the total amount of oxycodone inthe composition and about 50% of the total amount of acetaminophen inthe composition; and (b) at least one extended release portioncomprising about 75% of the total amount of oxycodone in thecomposition, about 50% of the total amount of acetaminophen in thecomposition, and about 35% to about 45%, by weight of the at least oneextended release portion, of an extended release polymer comprising apolyethylene oxide.

A further aspect of the disclosure provides a method for reducing therisk of acetaminophen-induced hepatic damage in a subject being treatedfor pain with a dosage regimen that comprises administering to thesubject at least two consecutive doses of a pharmaceutical compositioncomprising oxycodone and acetaminophen. The method comprises (a)administering a first dose of the pharmaceutical composition comprisingat least one extended release portion comprising acetaminophen,oxycodone or a combination thereof, and an extended release component tothe subject, wherein the composition maintains a therapeutic bloodplasma concentration of oxycodone of at least 5 ng/mL from about 0.75hours to about 10 hours after administration of the composition, andwherein at least about 90% of the acetaminophen is released from thecomposition by about 8 hours after administration of the compositionsuch that, by about 10 hours after administration of the composition,acetaminophen has a blood plasma concentration that is less than about30% of acetaminophen's maximum plasma concentration; and (b)administering a second dose of the pharmaceutical composition to thesubject at about 12 hours after administration of the first dose.

Yet another aspect of the disclosure encompasses a method for treatingpain in a subject in need thereof with a pharmaceutical composition thatcomprises oxycodone and acetaminophen. The method comprises orallyadministering to the subject an effective amount of the pharmaceuticalcomposition comprising at least one extended release portion comprisingoxycodone, acetaminophen or a combination thereof, and an extendedrelease component, wherein the composition maintains a therapeuticplasma concentration of oxycodone of at least about 5 ng/mL from about0.75 hour to about 10 hours after administration of the composition, andwherein at least about 90% of the acetaminophen is released from thecomposition by about 8 hours after administration of the compositionsuch that, by about 10 hours after administration of the composition,acetaminophen has a blood plasma concentration that is less than about30% of acetaminophen's maximum plasma concentration.

Other features and aspects of the disclosure are described in detailbelow.

REFERENCE TO COLOR FIGURES

This application file contains at least one drawing executed in color.Copies of this patent application publication with color drawings willbe provided by the Office upon request and payment of the necessary fee.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents the in vitro release profile of oxycodone fromoxycodone-acetaminophen bilayer tablets comprising either 15 or 30 mg ofoxycodone, 500 mg of acetaminophen (APAP), and either 35 wt % POLYOX®1105, 45 wt % POLYOX® 1105, or 45 wt % POLYOX® N60K, as indicated.

FIG. 2 shows the in vitro release profile of acetaminophen fromoxycodone-acetaminophen bilayer tablets comprising either 15 or 30 mg ofoxycodone, 500 mg of acetaminophen (APAP), and either 35 wt % POLYOX®1105, 45 wt % POLYOX® 1105, or 45 wt % POLYOX® N60K, as indicated.

FIG. 3 presents the in vitro release profile of oxycodone from bilayertablets comprising 7.5 mg of oxycodone and 325 mg of acetaminophen, andbilayer tablets comprising 15 mg of oxycodone and 650 mg ofacetaminophen, as indicated.

FIG. 4 presents the in vitro release profile of acetaminophen frombilayer tablets comprising 7.5 mg of oxycodone and 325 mg ofacetaminophen, and bilayer tablets comprising 15 mg of oxycodone and 650mg of acetaminophen, as indicated.

FIG. 5 is a graphical representation of the mean plasma oxycodoneconcentrations as a function of time after administration of a singledose of bilayer tablet comprising 15 mg oxycodone/500 mg acetaminophenand having fast, medium, or slow release properties as compared to animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredtwice at a 6 hr interval.

FIG. 6 is a graphical representation of the mean plasma acetaminophenconcentrations as a function of time after administration of a singledose of bilayer tablet comprising 15 mg oxycodone/500 mg acetaminophenand having fast, medium, or slow release properties as compared to animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredtwice at a 6 hr interval. The immediate release 7.5 oxycodone/325acetaminophen tablet dose was normalized.

FIG. 7 is a graphical representation of the mean plasma oxycodoneconcentrations as a function of time after administration of a singledose of bilayer tablet comprising 30 mg oxycodone/500 mg acetaminophenand having fast, medium, or slow release properties as compared to animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredtwice at a 6 hr interval. The immediate release 7.5 oxycodone/325acetaminophen tablet dose was normalized.

FIG. 8 is a graphical representation of the mean plasma acetaminophenconcentrations as a function of time after administration of a singledose of bilayer tablet comprising 30 mg oxycodone/500 mg acetaminophenand having fast, medium, or slow release properties as compared to animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredtwice at a 6 hr interval. The immediate release 7.5 oxycodone/325acetaminophen tablet dose was normalized.

FIG. 9 shows the mean plasma concentrations of oxycodone versus time bytreatment. Treatment A was one tablet of 15 mg oxycodone/650 mgacetaminophen administered orally under fed conditions. Treatment B wastwo tablets of 15 mg oxycodone/650 mg acetaminophen administered orallyone at a time under fed conditions. Treatment C was one tablet of animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredorally every 6 hours for 2 doses under fed conditions.

FIG. 10 presents the mean plasma concentrations of acetaminophen versustime by treatment. Treatment A was one tablet of 15 mg oxycodone/650 mgacetaminophen administered orally under fed conditions. Treatment B wastwo tablets of 15 mg oxycodone/650 mg acetaminophen administered orallyone at a time under fed conditions. Treatment C was one tablet of animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredorally every 6 hours for 2 doses under fed conditions.

FIG. 11 shows the mean plasma concentrations of oxycodone versus time bytreatment. Treatment A was one tablet of 15 mg oxycodone/650 mgacetaminophen administered orally every 12 hours for 4.5 days (9 doses)under fed conditions. Treatment B was two tablets of 15 mg oxycodone/650mg acetaminophen administered orally one at a time every 12 hours for4.5 days (9 doses) under fed conditions. Treatment C was two tablets ofan immediate release 7.5 oxycodone/325 acetaminophen tablet administeredorally every 6 hours for 4.5 days (18 doses) under fed conditions.

FIG. 12 shows the mean plasma concentrations of acetaminophen versustime by treatment. Treatment A was one tablet of 15 mg oxycodone/650 mgacetaminophen administered orally every 12 hours for 4.5 days (9 doses)under fed conditions. Treatment B was two tablets of 15 mg oxycodone/650mg acetaminophen administered orally one at a time every 12 hours for4.5 days (9 doses) under fed conditions. Treatment C was two tablets ofan immediate release 7.5 oxycodone/325 acetaminophen tablet administeredorally every 6 hours for 4.5 days (18 doses) under fed conditions.

FIG. 13 presents the mean plasma concentrations of oxycodone versus timeby treatment following oral administration of one tablet of 15 mgoxycodone/650 mg acetaminophen. Treatment A was under fed conditions.Treatment B was under fasted conditions.

FIG. 14 shows the mean plasma concentrations of oxycodone versus time bytreatment following oral administration of two tablets of 15 mgoxycodone/650 mg acetaminophen. Treatment A was under fed conditions.Treatment B was under fasted conditions.

FIG. 15 presents the mean plasma concentrations of acetaminophen versustime by treatment following oral administration of one tablet of 15 mgoxycodone/650 mg acetaminophen. Treatment A was under fed conditions.Treatment B was under fasted conditions.

FIG. 16 shows mean plasma concentrations of acetaminophen versus time bytreatment following oral administration of two tablets of 15 mgoxycodone/650 mg acetaminophen. Treatment A was under fed conditions.Treatment B was under fasted conditions.

FIG. 17 illustrates the in vitro release of oxycodone from a bilayertablet comprising 7.5 mg of oxycodone/325 mg of acetaminophen tested in0.1 N HCl at a paddle speed of 150 rpm containing 0%, 5%, 20%, or 40%ethanol. Plotted is the percent of oxycodone released over a period of 2hours.

FIG. 18 presents the in vitro release of acetaminophen from a bilayertablet comprising 7.5 mg of oxycodone/325 mg of acetaminophen tested in0.1 N HCl at a paddle speed of 150 rpm containing 0%, 5%, 20%, or 40%ethanol. Plotted is the percent of acetaminophen released over a 2 hourperiod.

FIG. 19 shows the mean plasma concentrations of oxycodone as a functionof time by treatment following oral administration of two tablets of 7.5mg of oxycodone/325 mg of acetaminophen. Treatment A was under fed (highfat) conditions. Treatment B was under fed (low fat) conditions.Treatment C was under fasted conditions.

FIG. 20 presents the mean plasma concentrations of acetaminophen as afunction of time by treatment following oral administration of twotablets of 7.5 mg of oxycodone/325 mg of acetaminophen. Treatment A wasunder fed (high fat) conditions. Treatment B was under fed (low fat)conditions. Treatment C was under fasted conditions.

FIG. 21 shows the mean plasma concentrations of oxycodone versus time bytreatment. Treatment A was one tablet of 7.5 mg oxycodone/325 mgacetaminophen administered orally under fasted conditions. Treatment Bwas two tablets of 7.5 mg oxycodone/325 mg acetaminophen administeredorally under fasted conditions. Treatment C was one tablet of animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredorally every 6 hours for 2 doses under fasted conditions. Treatment Dwas two tablets of an immediate release 7.5 oxycodone/325 acetaminophentablet administered orally every 6 hours for 2 doses under fastedconditions.

FIG. 22 presents the mean plasma concentrations of acetaminophen versustime by treatment. Treatment A was one tablet of 7.5 mg oxycodone/325 mgacetaminophen administered orally under fasted conditions. Treatment Bwas two tablets of 7.5 mg oxycodone/325 mg acetaminophen administeredorally under fasted conditions. Treatment C was one tablet of animmediate release 7.5 oxycodone/325 acetaminophen tablet administeredorally every 6 hours for 2 doses under fasted conditions. Treatment Dwas two tablets an immediate release 7.5 oxycodone/325 acetaminophentablet administered orally every 6 hours for 2 doses under fastedconditions.

FIG. 23 shows a deconvolution plot of the biphasic absorption ofoxycodone from tablets of the 7.5 mg oxycodone/325 mg acetaminophenformulation. The cumulative amount of oxycodone is plotted versus time.Circles represent one tablet of 7.5 mg oxycodone/325 mg acetaminophen;squares represent two tablets of 7.5 mg oxycodone/325 mg acetaminophen;and the immediate release 7.5 oxycodone/325 acetaminophen tablet isshown in a solid line with no symbols.

FIG. 24 presents a deconvolution plot of the biphasic absorption ofacetaminophen from tablets of the 7.5 mg oxycodone/325 mg acetaminophenformulation. The cumulative amount of acetaminophen is plotted versustime. Circles represent one tablet of 7.5 mg oxycodone/325 mgacetaminophen; triangles represent two tablets of 7.5 mg oxycodone/325mg acetaminophen; and squares represent the immediate release 7.5oxycodone/325 acetaminophen product.

FIG. 25 shows the mean plasma concentrations of oxycodone versus time bytreatment. Treatment A was one tablet of 7.5 mg oxycodone/325 mgacetaminophen administered orally every 12 hours for 4.5 days (9 doses)under fasted conditions. Treatment B was two tablets of 7.5 mgoxycodone/325 mg acetaminophen administered orally every 12 hours for4.5 days (9 doses) under fasted conditions. Treatment C was one tabletof an immediate release 7.5 oxycodone/325 acetaminophen tabletadministered orally every 6 hours for 4.5 days (18 doses) under fastedconditions.

FIG. 26 presents the mean plasma concentrations of acetaminophen versustime by treatment. Treatment A was one tablet of 7.5 mg oxycodone/325 mgacetaminophen administered orally every 12 hours for 4.5 days (9 doses)under fasted conditions. Treatment B was two tablets of 7.5 mgoxycodone/325 mg acetaminophen administered orally every 12 hours for4.5 days (9 doses) under fasted conditions. Treatment C was one tabletof an immediate release 7.5 oxycodone/325 acetaminophen tabletadministered orally every 6 hours for 4.5 days (18 doses) under fastedconditions.

FIG. 27A is a bar graph depicting the simulated fractional absorption ofacetaminophen in the upper GIT of a human subject after treatment of a7.5 mg oxycodone/325 mg acetaminophen immediate release formulation.FIG. 27B is a bar graph depicting the simulated fractional absorption ofacetaminophen in the upper GIT of a human subject after treatment of a7.5 mg oxycodone/325 mg acetaminophen immediate release formulation,wherein the formulation's transit time from the stomach through ileum 3has been doubled. FIG. 27C is a bar graph depicting the simulatedfractional absorption of acetaminophen in the upper GIT of a humansubject after treatment of a 7.5 mg oxycodone/325 mg acetaminophenimmediate release formulation, wherein the formulation's transit time inthe stomach has been increased by two hours.

FIG. 28A is a bar graph depicting the simulated fractional absorption ofoxycodone in the upper GIT of a human subject after treatment of a 7.5mg oxycodone/325 mg acetaminophen immediate release formulation. FIG.28B is a bar graph depicting the simulated fractional absorption ofoxycodone in the upper GIT of a human subject after treatment of a 7.5mg oxycodone/325 mg acetaminophen immediate release formulation, whereinthe formulation's transit time from the stomach through ileum 3 has beendoubled. FIG. 28C is a bar graph depicting the simulated fractionalabsorption of oxycodone in the upper GIT of a human subject aftertreatment of a 7.5 mg oxycodone/325 mg acetaminophen immediate releaseformulation, wherein the formulation's transit time in the stomach hasbeen increased by two hours.

FIG. 29A presents the mean plasma concentrations and Partial AUCs ofacetaminophen (e.g., AUC_(0-1.7h) and AUC_(1.7-48h)) versus time bytreatment: (1) Treatment B of Example 10, (2) Treatment C of Example 9,and (3) Treatment D of Example 10.

FIG. 29B presents the mean plasma concentrations and Partial AUCs ofoxycodone (e.g., AUC_(0-2.8h) and AUC_(2.8-48h)) versus time bytreatment: (1) Treatment B of Example 10, (2) Treatment C of Example 9,and (3) Treatment D of Example 10.

FIG. 30A presents the mean plasma concentrations and Partial AUCs ofoxycodone versus time for Treatment A of Example 4, Treatment A ofExample 6, and Treatment C of Example 4.

FIG. 30B presents the mean plasma concentrations and Partial AUCs ofacetaminophen versus time for Treatment A of Example 4, Treatment A ofExample 6, and Treatment C of Example 4.

FIG. 31 presents oxycodone dissolution data from crushed and intactimmediate release tablets containing 7.5 mg oxycodone and 325 mgacetaminophen.

FIGS. 32A and 32B present acetaminophen dissolution data from crushedand intact pharmaceutical formulations described herein containing atotal of 7.5 mg oxycodone and a total of 325 mg acetaminophen pertablet.

FIGS. 33A and 33B present oxycodone HCl dissolution data from crushedand intact pharmaceutical formulations described herein containing atotal of 7.5 mg oxycodone and a total of 325 mg acetaminophen pertablet.

FIG. 34 presents acetaminophen dissolution data for three pharmaceuticalformulations described herein. The dissolution data represents anextended release tablet with the immediate release data theoreticallyadded. For each formulation, the tablet contained a total of 9 mgoxycodone HCl and a total of 250 mg acetaminophen. The threepharmaceutical formulations contained 25% by weight POLYOX® 205, 1105,and N-60K, respectively.

FIG. 35 presents oxycodone HCl dissolution data for the threepharmaceutical formulations described in FIG. 34.

FIG. 36 presents acetaminophen dissolution data for three pharmaceuticalformulations described herein. The dissolution data represents anextended release tablet with the immediate release data theoreticallyadded. For each formulation, the tablet contained a total of 9 mgoxycodone HCl and a total of 250 mg acetaminophen. The threepharmaceutical formulations contained 45% by weight POLYOX® 205, 1105,and N-60K, respectively.

FIG. 37 presents oxycodone HCl dissolution data for the threepharmaceutical formulations described in FIG. 36.

FIG. 38 presents acetaminophen dissolution data for four pharmaceuticalformulations described herein. The dissolution data represents anextended release tablet with the immediate release data theoreticallyadded. For each formulation, the tablet contained a total of 9 mgoxycodone HCl and a total of 250 mg acetaminophen. The fourpharmaceutical compositions contained 25% by weight, 35% by weight, 45%by weight, and 55% by weight POLYOX® 1105, respectively.

FIG. 39 presents oxycodone HCl dissolution data for the threepharmaceutical formulations described in FIG. 38.

FIG. 40 presents the in vitro release of oxycodone from a bilayer tabletcomprising 7.5 mg of oxycodone/325 mg of acetaminophen tested in 0.1 NHCl at a paddle speed of 100 rpm containing 0%, 5%, 20%, or 40% ethanol.Plotted is the percent of oxycodone released over a period of 8 hours.

FIG. 41 presents the in vitro release of acetaminophen from a bilayertablet comprising 7.5 mg of oxycodone/325 mg of acetaminophen tested in0.1 N HCl at a paddle speed of 100 rpm containing 0%, 5%, 20%, or 40%ethanol. Plotted is the percent of acetaminophen released over a 8 hourperiod.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein is a combination product of oxycodone and acetaminophenthat has the desirable attributes of both IR and MR products. Theextended release pharmaceutical composition disclosed herein comprisesat least one extended release portion and, optionally, at least oneimmediate release portion. The extended release and immediate releaseportions may comprise oxycodone, acetaminophen, or combinations thereof.The at least one immediate release portion releases acetaminophen (APAP)and/or oxycodone instantly in an immediate release fashion that providesrapid onset for the attainment of therapeutically effective plasmaconcentrations within about the first 5 minutes, 10 minutes, 15 minutes,20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes,50 minutes, 55 minutes, or 60 minutes after administration of thecomposition. The at least one extended release portion releasesacetaminophen and/or oxycodone in an extended release fashion tomaintain plasma concentrations above the minimum effective concentrationfor about 8-12 hours. In addition, two other important features of thiscomposition are: 1) to allow the plasma concentrations of oxycodone tofall as rapidly as an immediate release formulation to provide the samerate of termination of drug effects as the immediate release product,and 2) to allow the concentrations of APAP to fall even quicker towardsthe later part of the dosing interval and bring down the levels of APAPlower than those of the immediate release product. The concentrations ofAPAP in the last quarter of the dosing interval are comparable to thepre-dose concentrations in a multiple dose setting, allowing for theglutathione synthase enzyme cycle to replenish the body's levels ofglutathione to avoid the formation of toxic intermediates withsubsequent doses of APAP. Moreover, the concentrations of APAP in thelater part of the dosing interval are lower than those present whenadministered a conventional extended release formulation. This featurehas been deliberately introduced to reduce the hepatic injury due toAPAP and is termed “APAP time-off”.

Abuse potential is a concern with any opioid product. The addition ofAPAP to the opioid, however, is likely to reduce the amount of abuse byillicit routes of administration, particularly intravenous or intranasaladministration. This deterrence is likely due to the bulk (grams) thatthe APAP provides as well as the relative aqueous insolubility comparedto freely soluble opioid salts. Further, APAP is known to be irritatingto nasal passages and to make drug abusers sneeze violently when theyare trying to snort it. In addition, embodiments disclosed herein may betamper resistant in that the compositions are difficult to crush foradministration intravenously or intranasally; difficult to extract withwater or alcohol because the mixture becomes too viscous for injectingor snorting; and resistant to dose dumping in alcohol.

In one embodiment, the pharmaceutical composition disclosed herein,therefore, provides: 1) rapid onset of analgesia within about 15, 30,45, or 60 minutes after administration of the composition mediated byboth oxycodone and APAP, with APAP providing maximal contribution duringthe early phase; 2) prolonged analgesia for the entire 12 hours period,mainly contributed by oxycodone, with minimal fluctuations during thisperiod; 3) relatively low levels of APAP toward end of dosing intervalto allow for recovery of the depleted hepatic glutathione system; 4) lowabuse quotient; and 5) abuse deterrence.

Headings included herein are simply for ease of reference, and are notintended to limit the disclosure in any way.

I. Definitions

Compounds useful in the compositions and methods include those describedherein in any of their pharmaceutically acceptable forms, includingisomers such as diastereomers and enantiomers, salts, solvates, andpolymorphs, as well as racemic mixtures and pure isomers of thecompounds described herein, where applicable.

When introducing elements of the various embodiment(s) of the presentdisclosure, the articles “a”, “an”, “the” and “said” are intended tomean that there are one or more of the elements. The terms “comprising”,“including” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements.

The use of individual numerical values are stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Thus, as a generalmatter, “about” or “approximately” broaden the numerical value. Also,the disclosure of ranges is intended as a continuous range includingevery value between the minimum and maximum values plus the broadeningof the range afforded by the use of the term “about” or “approximately.”Consequently, recitation of ranges of values herein are merely intendedto serve as a shorthand method of referring individually to eachseparate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein.

The term “abuse quotient” for a pharmaceutical composition as usedherein is the numerical value obtained via dividing the C_(max) for adrug by the T_(max) for the same drug. Generally speaking, the abusequotient provides a means for predicting the degree of addictiveness ofa given pharmaceutical composition. Pharmaceutical compositions withlower abuse quotients typically are less addictive compared topharmaceutical compositions with higher abuse quotients.

The term “active agent” or “drug,” as used herein, refers to anychemical that elicits a biochemical response when administered to ahuman or an animal. The drug may act as a substrate or product of abiochemical reaction, or the drug may interact with a cell receptor andelicit a physiological response, or the drug may bind with and block areceptor from eliciting a physiological response.

The term “bioequivalent,” as used herein, refers to two compositions,products or methods where the 90% Confidence Intervals (CI) for AUC,partial AUC and/or C_(max) are between 0.80 to 1.25.

The term “bulk density,” as used herein, refers to a property of powdersand is defined as the mass of many particles of the material divided bythe total volume they occupy. The total volume includes particle volume,inter-particle void volume and internal pore volume.

The term “content uniformity,” as used herein refers to the testing ofcompressed tablets to provide an assessment of how uniformly themicronized or submicron active ingredient is dispersed in the powdermixture. Content uniformity is measured by use of USP Method (GeneralChapters, Uniformity of Dosage Forms), unless otherwise indicated. Aplurality refers to five, ten or more tablet compositions.

The term “friability,” as used herein, refers to the ease with which atablet will break or fracture. The test for friability is a standardtest known to one skilled in the art. Friability is measured understandardized conditions by weighing out a certain number of tablets(generally 20 tablets or less), placing them in a rotating Plexiglasdrum in which they are lifted during replicate revolutions by a radiallever, and then dropped approximately 8 inches. After replicaterevolutions (typically 100 revolutions at 25 rpm), the tablets arereweighed and the percentage of composition abraded or chipped iscalculated.

The term “ER” as used herein refers to extended release. The phrases“extended release layer,” “ER layer,” “ER portion,” and “extendedrelease portion” are used interchangeable in this document. Further, asused herein the “extended release layer,” “ER layer,” “ER portion,” and“extended release portion” can be either (i) a discrete part(s) of thepharmaceutical composition, (ii) integrated within the pharmaceuticalcomposition, or (iii) a combination thereof.

The term “IR” as used herein refers to immediate release. The phrases“immediate release layer,” “IR layer,” “IR portion” and “immediaterelease portion” are used interchangeable in this document. In addition,as used herein the “immediate release layer,” “IR layer,” “IR portion”and “immediate release portion” can be either (i) a discrete part(s) ofthe pharmaceutical composition, (ii) integrated within thepharmaceutical composition, or (iii) a combination thereof.

The term “half life” as used herein refers to the time required for adrug's blood or plasma concentration to decrease by one half. Thisdecrease in drug concentration is a reflection of its excretion orelimination after absorption is complete and distribution has reached anequilibrium or quasi equilibrium state. The half life of a drug in theblood may be determined graphically off of a pharmacokinetic plot of adrug's blood-concentration time plot, typically after intravenousadministration to a sample population. The half life can also bedetermined using mathematical calculations that are well known in theart. Further, as used herein the term “half life” also includes the“apparent half-life” of a drug. The apparent half life may be acomposite number that accounts for contributions from other processesbesides elimination, such as absorption, reuptake, or enterohepaticrecycling.

“Optional” or “optionally” means that the subsequently describedelement, component or circumstance may or may not occur, so that thedescription includes instances where the element, component, orcircumstance occurs and instances where it does not.

“Partial AUC” means an area under the drug concentration-time curve(AUC) calculated using linear trapezoidal summation for a specifiedinterval of time, for example, AUC_((0-1hr)) AUC_((0-2hr)),AUC_((0-4hr)), AUC_((0-6hr)), AUC_((0-8hr)),AUC_((0-(Tmax of IR product+2SD))), AUC_((0-(x)hr)), AUC_((x-yhr)),AUC_((Tmax-t)), AUC(0-(t)hr), AUC_((Tmax of IR product+2SD)-t)), orAUC_((0-∞)).

A drug “release rate,” as used herein, refers to the quantity of drugreleased from a dosage form or pharmaceutical composition per unit time,e.g., milligrams of drug released per hour (mg/hr). Drug release ratesfor drug dosage forms are typically measured as an in vitro rate ofdissolution, i.e., a quantity of drug released from the dosage form orpharmaceutical composition per unit time measured under appropriateconditions and in a suitable fluid. The specific results of dissolutiontests claimed herein are performed on dosage forms or pharmaceuticalcompositions immersed in 900 mL of 0.1 N HCl using a USP Type IIapparatus at a paddle speed of either about 100 rpm or about 150 rpm anda constant temperature of about 37° C. Suitable aliquots of the releaserate solutions are tested to determine the amount of drug released fromthe dosage form or pharmaceutical composition. For example, the drug canbe assayed or injected into a chromatographic system to quantify theamounts of drug released during the testing intervals.

The terms “subject” or “patient” are used interchangeably herein andrefer to a vertebrate, preferably a mammal. Mammals include, but are notlimited to, humans.

The term “tap density” or “tapped density,” as used herein, refers to ameasure of the density of a powder. The tapped density of apharmaceutical powder is determined using a tapped density tester, whichis set to tap the powder at a fixed impact force and frequency. Tappeddensity by the USP method is determined by a linear progression of thenumber of taps.

II. Pharmaceutical Compositions Comprising Extended and ImmediateRelease Portions Comprising Oxycodone and Acetaminophen

The present disclosure provides pharmaceutical compositions comprisingoxycodone and its pharmaceutical salts and acetaminophen. Thepharmaceutical composition comprises at least one extended releaseportion comprising oxycodone, acetaminophen or a combination thereof,and an extended release component. The pharmaceutical composition mayalso comprise at least one immediate release portion comprisingoxycodone, acetaminophen, or a combination thereof. The compositionsdisclosed herein are formulated to deliver therapeutic concentrations ofoxycodone and acetaminophen within about the first hour after oraladministration and to maintain therapeutic concentrations of oxycodoneand acetaminophen for an extended period of time (e.g., 10-12 hours).

The total amount of oxycodone present in the pharmaceutical compositioncan and will vary. In some embodiments, the total amount of oxycodonepresent in the pharmaceutical composition may range from about 2 mg toabout 160 mg, about 5 mg to about 75 mg, about 5 mg to about 40 mg, orabout 10 mg to about 30 mg. In another embodiment, the total amount ofoxycodone in the pharmaceutical composition may range from about 5 mg toabout 30 mg. In various embodiments, the total amount of oxycodonepresent in the pharmaceutical composition may be about 5 mg, 5.5 mg, 6.0mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 110 mg, 120 mg, 130 mg,140 mg, 150 mg, or 160 mg. In one embodiment, the total amount ofoxycodone in the pharmaceutical composition may be about 30 mg. Inanother embodiment, the total amount of oxycodone in the pharmaceuticalcomposition may be about 15 mg. In still another embodiment, the totalamount of oxycodone in the pharmaceutical composition may be about 7.5mg.

The total amount of acetaminophen present in the pharmaceuticalcomposition also may vary. In one embodiment, the total amount ofacetaminophen present in the pharmaceutical composition may range fromabout 80 mg to about 1600 mg. In another embodiment, the total amount ofacetaminophen present in the pharmaceutical composition may be about 250mg to about 1300 mg. In a further embodiment, the total amount ofacetaminophen present in the pharmaceutical composition may be about 300mg to about 600 mg. In yet another embodiment, the total amount ofacetaminophen present in the pharmaceutical composition may be about 325mg to about 650 mg. In another embodiment, the total amount ofacetaminophen present in the pharmaceutical composition may be about 150mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 600 mg, 650mg, 700 mg, 750 mg, 1000 mg, or 1300 mg. In one embodiment, the totalamount of acetaminophen in the pharmaceutical composition may be about650 mg. In another embodiment, the total amount of acetaminophen in thepharmaceutical composition may be about 500 mg. In yet anotherembodiment, the total amount of acetaminophen in the pharmaceuticalcomposition may be about 325 mg.

(a) Immediate Release Portion

The pharmaceutical composition disclosed herein may comprise at leastone immediate release portion. In one embodiment, the at least oneimmediate release portion may comprise oxycodone. In another embodiment,the at least one immediate release portion may comprise acetaminophen.In a further embodiment, the at least one immediate release portion maycomprise oxycodone and acetaminophen.

The at least one immediate release portion of the pharmaceuticalcomposition is designed to release more than 80%, more than 90%, oressentially all of the oxycodone and/or acetaminophen in the at leastone immediate release portion(s) within about one hour. In oneembodiment, more than 80%, more than 90%, or essentially all of theoxycodone and/or acetaminophen in the at least one immediate releaseportion(s) may be released in less than about 45 min. In anotherembodiment, more than 80%, more than 90%, or essentially all of theoxycodone and/or acetaminophen in the at least one immediate releaseportion(s) may be released in less that about 30 min. In a furtherembodiment, more than 80%, more than 90%, or essentially all of theoxycodone and/or acetaminophen in the at least one immediate releaseportion(s) may be released in less than about 20 min. In yet anotherembodiment, more than 80%, more than 90%, or essentially all of theoxycodone and/or acetaminophen in the at least one immediate releaseportion(s) may be released in less that about 15 min. In an alternateembodiment, more than 80%, more than 90%, or essentially all of theoxycodone and/or acetaminophen in the at least one immediate releaseportion(s) may be released in less that about 10 min. In yet anotherembodiment, more than 80%, more than 90%, or essentially all of theoxycodone and/or acetaminophen in the at least one immediate releaseportion may be released in less that about 5 min.

(i) Oxycodone

The at least one immediate release portion of the pharmaceuticalcomposition may comprise oxycodone. The amount of oxycodone in the atleast one immediate release portion of the pharmaceutical compositioncan and will vary. In one embodiment, the amount of oxycodone in the atleast one immediate release portion may range from about 1 mg to about40 mg. In a further embodiment, the amount of oxycodone in the at leastone immediate release portion of the pharmaceutical composition mayrange from about 1 mg to about 7.5 mg. In another embodiment, the amountof oxycodone in the at least one immediate release portion may rangefrom about 7.5 mg to about 15 mg. In yet another embodiment, the amountof oxycodone in the at least one immediate release portion may rangefrom about 15 mg to about 40 mg. In various embodiments, the amount ofoxycodone in the at least one immediate release portion may be about1.25 mg, 1.3 mg, 1.325 mg, 1.35 mg, 1.375 mg, 1.4 mg, 1.425 mg, 1.45 mg,1.475 mg, 1.5 mg, 1.525 mg, 1.55 mg, 1.575 mg, 1.6 mg, 1.625 mg, 1.65mg, 1.675 mg, 1.7 mg, 1.725 mg, 1.75 mg, 1.775 mg, 1.8 mg, 1.825 mg,1.85 mg, 1.875 mg, 1.9 mg, 1.925 mg, 1.95 mg, 1.975 mg, 2.0 mg, 2.25 mg,2.5 mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5mg, 4.75 mg, 5.0 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6.0 mg, 6.25 mg, 6.5 mg,6.75 mg, 7.0 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8.0 mg, 8.25 mg, 8.5 mg, 8.75mg, 9.0 mg, 9.25 mg, 9.5 mg, 9.75 mg, 10.0 mg, 11.0 mg, 12.0 mg, 13.0mg, 14.0 mg, 15.0 mg, 20.0 mg, or 40.0 mg. In one embodiment, the amountof oxycodone in the at least one immediate release portion may rangefrom about 7.0 mg and about 8.0 mg, for example, about 7.5 mg. Inanother embodiment, the amount of oxycodone in the at least oneimmediate release portion may be between about 3.0 mg and about 4.0 mg,for example, about 3.75 mg. In still another embodiment, the amount ofopioid in the at least one immediate release portion may be betweenabout 1.0 mg and about 2.0 mg, for example, about 1.875 mg.

The amount of oxycodone present in the at least one immediate releaseportion(s) may be expressed as a percentage (w/w) of the total amount ofoxycodone in the pharmaceutical composition. In one embodiment, the atleast one immediate release portion may comprise from about 20% to about30% (w/w) of the total amount of oxycodone present in the pharmaceuticalcomposition. In certain embodiments, the percentage of oxycodone presentin the at least one immediate release portion of the pharmaceuticalcomposition may be about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,29%, or 30% (w/w) of the total amount of oxycodone. In anotherembodiment, the percentage of oxycodone present in the at least oneimmediate release portion of the pharmaceutical composition may be about25% (w/w) of the total amount of oxycodone present in the pharmaceuticalcomposition.

The amount of oxycodone in the at least one immediate release portionalso may be expressed as a percentage (w/w) of the total weight of theimmediate release portion(s) of the pharmaceutical composition. In oneembodiment, the amount of oxycodone in an immediate release portion mayrange from about 0.2 (w/w) to about 15.0% (w/w) of the total weight ofsuch immediate release portion of the pharmaceutical composition. Inanother embodiment, the amount of oxycodone in an immediate releaseportion may range from about 0.5% (w/w) to about 2% (w/w) of the totalweight of such immediate release portion. In various embodiments, animmediate release portion may comprise an amount of oxycodone that isapproximately 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%,1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%,2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.25%, 3.5%, 3.75%,4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%,6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0%, 8.25%, 8.5%, 8.75%, 9.0%, 9.25%,9.5%, 9.75%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%(w/w) of the total weight of such immediate release portion of thepharmaceutical composition. In yet another embodiment, the amount ofoxycodone in an immediate release portion may be about 0.5% (w/w) toabout 1.0% (w/w) of the total weight of such immediate release portionof the pharmaceutical composition.

In some embodiments, the oxycodone of the at least one immediate releaseportion(s) of the pharmaceutical composition may be in the form ofparticles comprising oxycodone and at least one excipient. The at leastone immediate release portion, therefore, may comprise particles ofoxycodone that are admixed with the acetaminophen and optionalexcipient(s). Suitable oxycodone particles are described in co-pendingapplication U.S. application Ser. No. 13/166,770, filed Jun. 22, 2011,which is incorporated herein by reference in its entirety. The oxycodoneparticles may be coated or uncoated. The average size or averagediameter of the particles may vary. In general, the average diameter ofthe particles may range from about 50 microns to about 2000 microns,from about 100 microns to about 1000 microns, or from about 150 micronsto about 200 microns. In one embodiment, the maximum diameter of about50% of the particles (d50) may be about 40 microns, 50 microns, 100microns, 150 microns, 200 microns, 250 microns, 300 microns, 400microns, or 500 microns. In another embodiment, the maximum diameter ofabout 90% of the particles (d90) may be about 100 microns, 150 microns,200 microns, 250 microns, 300 microns, 400 microns, or 500 microns.

(ii) Acetaminophen

The at least one immediate release portion of the pharmaceuticalcomposition may comprise acetaminophen. The amount of acetaminophen inthe at least one immediate release portion(s) can and will vary. In oneembodiment, the amount of acetaminophen in the at least one immediaterelease portion of the pharmaceutical composition may range from about40 mg to about 800 mg. In still another embodiment, the at least oneimmediate release portion of the pharmaceutical composition may comprisefrom about 100 mg to about 600 mg of acetaminophen. In anotherembodiment, the at least one immediate release portion may comprise fromabout 125 mg to about 400 mg of acetaminophen. In a further embodiment,the amount of acetaminophen in the at least one immediate releaseportion may range from about 160 mg to about 325 mg. In yet anotherembodiment, the amount of acetaminophen in the at least one immediaterelease portion may be about 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145mg, 150 mg, 155 mg, 160 mg, 162.5 mg, 165 mg, 170 mg, 175 mg, 180 mg,185 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg,260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg,340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 500 mg, 520 mg,650 mg, or 780 mg. In one embodiment, the at least one immediate releaseportion may comprise about 325 mg of acetaminophen. In anotherembodiment, the amount of acetaminophen in the at least one immediaterelease portion may be about 250 mg. In yet another embodiment, theamount of acetaminophen in the at least one immediate release portionmay be about 162.5 mg. In still another embodiment, the amount ofacetaminophen in the at least one immediate release portion may be about125 mg.

The at least one immediate release portion(s) of the pharmaceuticalcomposition may comprise from about 40% to about 60% (w/w) of the totalamount of acetaminophen present in the pharmaceutical composition. Theamount of acetaminophen in the at least one immediate release portionmay be about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% (w/w) of the total amountof acetaminophen present in the pharmaceutical composition. In oneembodiment, the percentage of acetaminophen present in the at least oneimmediate release portion may be about 50% (w/w) of the total amount ofacetaminophen present in the pharmaceutical composition.

The amount of acetaminophen in an immediate release portion(s) of thepharmaceutical composition may range from about 20% (w/w) to about 95%(w/w) of the total weight of such immediate release portion of thecomposition. In various embodiments, an immediate release portion maycomprise an amount of acetaminophen that is approximately about 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or95% (w/w) of the total weight of such immediate release portion. In oneembodiment, the amount of acetaminophen in an immediate release portionmay range from about 70% to about 80% (w/w) of the total weight of suchimmediate release portion of the pharmaceutical composition.

(iii) Excipients

The at least one immediate release portion(s) of the pharmaceuticalcomposition may further comprise at least one excipient. Suitableexcipients include binders, fillers, disintegrants, lubricants,antioxidants, chelating agents, and color agents.

In one embodiment, the at least one immediate release portion(s) of thepharmaceutical composition may comprise at least one binder. Suitablebinders include, without limit, starches (including corn starch andpregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, polyols, polyvinylalcohols,C12-C18 fatty acid alcohols, waxes, gums (e.g., guar gum, arabic gum,acacia gum, xantham gum, etc.), gelatin, pectin, sodium alginate,polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxylcellulose,methylcellulose, microcrystalline cellulose, ethylcellulose,hydroxyethyl cellulose, and the like), polyacrylamides, andpolyvinyloxoazolidone. In one embodiment, the amount of binder orbinders in an immediate release portion of the pharmaceuticalcomposition may range from about 5% to about 10% (w/w) of the totalweight of such immediate release portion. In various embodiments, animmediate release portion of the pharmaceutical composition may compriseat least one binder that is present in an amount that is about 5.0%,5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.1%, 7.2%, 7.3%,7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%,8.6%, 8.7%, 8.8%, 8.9%, or 9.0% (w/w) of such immediate release portionof the composition.

In another embodiment, the at least one immediate release portion(s) ofthe pharmaceutical composition may comprise at least one filler.Suitable fillers include but are not limited to microcrystallinecellulose (MCC), dibasic calcium phosphate, tribasic calcium phosphate,magnesium carbonate, magnesium oxide, calcium silicate, magnesiumaluminum silicate, silicon dioxide, titanium dioxide, alumina, talc,kaolin, polyvinylpyrrolidone, dibasic calcium sulfate, tribasic calciumsulfate, starch, calcium carbonate, magnesium carbonate, carbohydrates,modified starches, lactose, sucrose, dextrose, mannitol, sorbitol, andinorganic compounds. In one embodiment, the amount of filler or fillersin an immediate release portion may range from about 1.0% to about 10.0%(w/w) of the total weight of such immediate release portion. In variousembodiments, an immediate release portion of the pharmaceuticalcomposition may comprise at least one filler that is present in anamount that is about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%,5.0%, 5.5%, 6.0%, 6.2%, 6.4%, 6.5%. 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%,7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%,8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%,9.6%, 9.7%, 9.8%, 9.9%, or 10.0%, of such immediate release portion ofthe pharmaceutical composition.

In still another embodiment, the at least one immediate releaseportion(s) of the pharmaceutical composition may further comprise adisintegrant. The disintegrant may be selected from the group consistingof croscarmellose sodium, crospovidone, alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium, lowsubstituted hydroxypropylcellulose, microcrystalline cellulose, andsodium starch glycolate. In one embodiment, the amount of disintegrantin an immediate release portion may range from about 2.0% to about 15.0%(w/w) of the total weight of such immediate release portion. In someembodiments, the amount of disintegrant in an immediate release portionmay be about 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 5.2%, 5.4%, 5.6%. 5.8%,6.0%, 6.2%, 6.4%. 6.6%, 6.8%, or 7.0% (w/w) of such immediate releaseportion of the pharmaceutical composition.

In a further embodiment, the at least one immediate release portion(s)of the pharmaceutical composition may further comprise a lubricant.Useful lubricants include magnesium stearate, calcium stearate, stearicacid, and hydrogenated vegetable oil (preferably comprised ofhydrogenated and refined triglycerides of stearic and palmitic acids).The lubricant may be present in an amount ranging from about 0.1% toabout 3.0% (w/w) of the total weight of an immediate release portion. Incertain embodiments, the amount of lubricant in at least one immediaterelease portion may be about 0.25%, 0.5%, 0.75%, 1.0%, 1.5%, 1.55%,1.6%, 1.65%, 1.7%, 1.75%, 1.80%, 1.85%, 1.90%, or 2.0% (w/w) of thetotal weight of such immediate release portion.

In yet another embodiment, the at least one immediate release portion(s)of the pharmaceutical composition may comprise at least one antioxidant.Suitable antioxidants include, without limitation, ascorbic acid, citricacid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, and propylgallate.The amount of antioxidant present in an immediate release portion of thepharmaceutical composition may range from about 0.01% to about 4.0%(w/w), or from about 0.02% to about 0.10% (w/w) of the total weight ofsuch immediate release portion. In various embodiments, the amount ofantioxidant present in an immediate release portion of thepharmaceutical composition may be about 0.01%, 0.02%, 0.03%, 0.04%,0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.12%, 0.14%, 0.16%, 0.18%.0.20%, 0.25%, 0.50%, 0.75%, 1.00%, 1.50%, or 2.00% (w/w) of the totalweight of such immediate release portion.

In still another embodiment, the at least one immediate releaseportion(s) of the pharmaceutical composition may comprise at least onechelating agent. Suitable chelating agents include ethylenediaminetetracetic acid (EDTA) and its salts,N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid(NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,1,4,7,10-tetraazacyclodo-decane-N,N′,N″,N′″-tetraacetic acid,1,4,7,10-tetraaza-cyclododecane-N,N′,N″-triacetic acid,1,4,7-tris(carboxymethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazocyclodecane,1,4,7-triazacyclonane-N,N′,N″-triacetic acid,1,4,8,11-tetraazacyclotetra-decane-N,N′,N″,N′″-tetraacetic acid;diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,bis(aminoethanethiol)carboxylic acid, triethylenetetraamine-hexaaceticacid, and 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid. In oneembodiment, the chelating agent may be the sodium salt of EDTA. Theamount of chelating agent present in an immediate release portion of thepharmaceutical composition may range from about 0.001% to about 0.20%(w/w) of such immediate release portion. In some embodiments, the amountof chelating agent present in an immediate release portion of thepharmaceutical composition may be about 0.001%, 0.002%, 0.003%, 0.004%,0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w/w) of the total weight ofsuch immediate release portion.

In an alternate embodiment, the at least one immediate release portionof the pharmaceutical composition may comprise a color agent. Suitablecolor additives include, but are not limited to, food, drug and cosmeticcolors (FD&C), drug and cosmetic colors (D&C), and external drug andcosmetic colors (Ext. D&C). In various embodiments, the amount of coloragent present in an immediate release portion may range from about 2.0%to about 5.0% (w/w) of the total weight of such immediate releaseportion of the composition. In other embodiments, the amount of coloragent present in an immediate release portion may be about 1.0%, 1.5%,2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% (w/w) of the total weight ofsuch immediate release portion.

(b) Extended Release Portion

The pharmaceutical composition disclosed herein comprises at least oneextended release portion. The at least one extended release portion maycomprise oxycodone, acetaminophen, or a combination thereof. Theextended release portion(s) further comprise(s) an extended releasecomponent. The extended release component may comprise at least oneextended release polymer.

The at least one extended release portion of the pharmaceuticalcomposition is designed to release the active agents over an extendedperiod of time. In general, the extended release portion(s) providesrelease of oxycodone and/or acetaminophen for a period of time rangingfrom at least about 3 hours (hrs) to at least about 12 hrs. In oneembodiment, the extended release portion(s) may release oxycodone and/oracetaminophen over a period of at least about 5 hrs, or over a period atleast about 6 hrs. In another embodiment, oxycodone and/or acetaminophenmay be released from the extended release portion(s) over a period of atleast about 7 hrs, or over a period of at least about 8 hrs. In stillanother embodiment, the extended release portion(s) may releaseoxycodone and/or acetaminophen over a period of at least about 9 hrs, orover a period of at least about 10 hrs. In a further embodiment,oxycodone and/or acetaminophen may be released from the extended releaseportion(s) over a period of at least about 11 hrs, or over a period ofat least about 12 hrs.

(i) Oxycodone

The amount of oxycodone present in the at least one extended releaseportion(s) can and will vary. In one embodiment, the amount of oxycodonein the at least one extended release portion may range from about 1 mgto about 120 mg. In a further embodiment, the at least one extendedrelease portion of the pharmaceutical composition may comprise about 1mg to about 22.5 mg of oxycodone. In another embodiment, the amount ofoxycodone in the at least one extended release portion may be about 10mg to about 30 mg. In yet another embodiment, the amount of oxycodone inthe at least one extended release portion may be about 30 mg to about 60mg. In another embodiment, the at least one extended release portioncomprises about 5 mg to about 7 mg of oxycodone. In a furtherembodiment, the amount of oxycodone may be about 5.625 mg to about 11.25mg. In an additional embodiment, the amount of oxycodone may be about 10mg to about 12.5 mg. In a further embodiment, the amount of oxycodonemay be about 12 mg to about 18 mg. In another embodiment, the amount ofoxycodone in the at least one extended release portion may be about 20mg to about 25 mg. In yet another embodiment, the amount of oxycodonemay be about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5mg, 5.0 mg, 5.5 mg, 5.625 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg,8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.25 mg, 11.5 mg,12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg,16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg, 18.0 mg, 18.5 mg, 19.0 mg, 19.5 mg,20.0 mg, 22.5 mg, or 25 mg. In one embodiment, the amount of oxycodonein the at least one extended release portion may be from about 22 mg toabout 23 mg, for example, about 22.5 mg. In another embodiment, theamount of oxycodone in the at least one extended release portion may beabout 10 mg to about 12 mg, for example, about 11.25 mg. In stillanother embodiment, the amount of opioid in the at least one extendedrelease portion may be from about 5 mg to about 6 mg, for example, about5.625 mg.

The amount of oxycodone present in the at least one extended releaseportion(s) may be expressed as a percentage of the total amount ofoxycodone in the pharmaceutical composition. In one embodiment, the atleast one extended release portion of the pharmaceutical compositioncomprises from about 70% to about 80% (w/w) of the total amount ofoxycodone present in the pharmaceutical composition. In certainembodiments, the percentage of oxycodone present in the at least oneextended release portion of the pharmaceutical composition may be about70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80% of the totalamount of oxycodone. In one embodiment, the percentage of oxycodonepresent in the at least one extended release portion of thepharmaceutical composition may be about 75% of the total amount ofoxycodone present in the pharmaceutical composition.

The amount of oxycodone in the extended release portion(s) also may beexpressed as a percentage of the total weight of the extended releaseportion(s) of the pharmaceutical composition. In one embodiment, theamount of oxycodone in an extended release portion may range from about0.5% to about 5.0% (w/w) of the total weight of the such extendedrelease portion of the pharmaceutical composition. In variousembodiments, an extended release portion may comprise an amount ofoxycodone that is approximately 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%,1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%,2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%,3.6%, 3.7%, 3.8%, 3.9%, or 4.0% (w/w) of the total weight of suchextended release portion of the pharmaceutical composition. In oneembodiment, the amount of oxycodone in an extended release portioncomprises about 0.5% to about 2% (w/w) of the total weight of suchextended release portion of the pharmaceutical composition.

In some embodiments, the oxycodone of the extended release portion(s)may be in the form of particles comprising oxycodone and at least oneexcipient. Thus, the at least one extended release portion may compriseparticles of oxycodone which are admixed with the acetaminophen and theextended release component, both of which are detailed below, as well asoptional excipients. Suitable oxycodone particles are described inco-pending application U.S. application Ser. No. 13/166,770, filed Jun.22, 2011, which is incorporated herein by reference in its entirety. Theoxycodone particles may be coated or uncoated. The average size oraverage diameter of the particles may vary. In general, the averagediameter of the particles may range from about 50 microns to about 2000microns, from about 100 microns to about 1000 microns, or from about 150microns to about 200 microns. In one embodiment, the maximum diameter ofabout 50% of the particles (d50) may be about 40 microns, 50 microns,100 microns, 150 microns, 200 microns, 250 microns, 300 microns, 400microns, or 500 microns. In another embodiment, the maximum diameter ofabout 90% of the particles (d90) may be about 100 microns, 150 microns,200 microns, 250 microns, 300 microns, 400 microns, or 500 microns.

(ii) Acetaminophen

The extended release portion(s) of the pharmaceutical composition maycomprise acetaminophen. The amount of acetaminophen in the extendedrelease portion(s) of the pharmaceutical composition can and will vary.In one embodiment, the at least one extended release portion of thepharmaceutical composition may comprise an amount of acetaminophenranging from about 40 mg to about 800 mg. In still another embodiment,the at least one extended release portion of the pharmaceuticalcomposition may comprise from about 100 mg to about 600 mg ofacetaminophen. In another embodiment, the at least one extended releaseportion may comprise from about 125 mg to about 400 mg of acetaminophen.In a further embodiment, the amount of acetaminophen in the at least oneextended release portion may range from about 160 mg to about 325 mg. Inyet another embodiment, the amount of acetaminophen in the at least oneextended release portion may be about 100 mg, 110 mg, 120 mg, 125 mg,130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 162.5 mg, 165mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 210 mg, 220mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310mg, 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390mg, 400 mg, 500 mg, 520 mg, 650 mg, or 780 mg. In one embodiment, the atleast one extended release portion comprises about 325 mg ofacetaminophen. In another embodiment, the amount of acetaminophen in theat least one extended release portion may be about 250 mg. In yetanother embodiment, the amount of acetaminophen in the at least oneextended release portion may be about 162.5 mg. In still anotherembodiment, the amount of acetaminophen in the at least one extendedrelease portion may be about 125 mg.

The extended release portion(s) of the pharmaceutical composition maycomprise from about 40% to about 60% of the total amount ofacetaminophen present in the pharmaceutical composition. The amount ofacetaminophen in the at least one extended release portion may be about40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%,54%, 55%, 56%, 57%, 58%, 59%, or 60% (w/w) of the total amount ofacetaminophen present in the pharmaceutical composition. In oneembodiment, the percentage of acetaminophen present in the extendedrelease portion(s) of the pharmaceutical composition may be about 50%(w/w) of the total amount of acetaminophen.

The amount of acetaminophen in an extended release portion of thepharmaceutical composition may range from about 15% to about 60% (w/w)of the total weight of such extended release portion of thepharmaceutical composition. In various embodiments, an extended releaseportion may comprise an amount of acetaminophen that is approximatelyabout 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%,28%, 30%, 32%, 35%, 37%, 40%, 42%, 45%, 47%, 50%, 52%, or 55% (w/w) ofthe total weight of such extended release portion. In one embodiment,the amount of acetaminophen in an extended release portion may rangefrom about 20% to about 40% (w/w) of the total weight of such extendedrelease portion of the pharmaceutical composition.

(iii) Extended Release Component

The extended release portion(s) of the pharmaceutical composition alsocomprise(s) an extended release component. Suitable extended releasecomponents include polymers, resins, hydrocolloids, hydrogels, and thelike.

In one embodiment, the extended release component may comprise at leastone extended release polymer. Suitable polymers for inclusion in the atleast one extended release portion of the pharmaceutical composition maybe linear, branched, dendrimeric, or star polymers, and includesynthetic hydrophilic polymers as well as semi-synthetic and naturallyoccurring hydrophilic polymers. The polymers may be homopolymers orcopolymers, such as random copolymers, block copolymers, and graftcopolymers. Suitable hydrophilic polymers include, but are not limitedto: polyalkylene oxides, particularly poly(ethylene oxide), polyethyleneglycol and poly(ethylene oxide)-poly(propylene oxide) copolymers;cellulosic polymers, such as methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and carboxymethylcellulose,microcrystalline cellulose, and polysaccharides and their derivatives;acrylic acid and methacrylic acid polymers, copolymers and estersthereof, preferably formed from acrylic acid, methacrylic acid, methylacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, andcopolymers thereof, with each other or with additional acrylate speciessuch as aminoethyl acrylate; maleic anhydride copolymers; polymaleicacid; poly(acrylamides) such as polyacrylamide per se,poly(methacrylamide), poly(dimethylacrylamide), andpoly(N-isopropyl-acrylamide); polyalkylene oxides; poly(olefinicalcohol)s such as poly(vinyl alcohol); poly(N-vinyl lactams) such aspoly(vinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymersthereof; polyols such as glycerol, polyglycerol (particularly highlybranched polyglycerol), propylene glycol and trimethylene glycolsubstituted with one or more polyalkylene oxides, e.g., mono-, di- andtri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propyleneglycol, and mono- and di-polyoxyethylated trimethylene glycol;polyoxyethylated sorbitol and polyoxyethylated glucose; polyoxazolines,including poly(methyloxazoline) and poly(ethyloxazoline);polyvinylamines; polyvinylacetates, including polyvinylacetate per se aswell as ethylene-vinyl acetate copolymers, polyvinyl acetate phthalate,and the like, polyimines, such as polyethyleneimine; starch andstarch-based polymers; polyurethane hydrogels; chitosan; polysaccharidegums; xanthan gum; zein; and shellac, ammoniated shellac, shellac-acetylalcohol, and shellac n-butyl stearate. The polymers may be usedindividually or in combination. Certain combinations will often providea more controlled release of oxycodone and acetaminophen than theircomponents when used individually. Suitable combinations includecellulose-based polymers combined with gums, such as hydroxyethylcellulose or hydroxypropyl cellulose combined with xanthan gum, andpoly(ethylene oxide) combined with xanthan gum.

In one embodiment, the extended release polymer(s) may be a cellulosicpolymer, such as an alkyl substituted cellulose derivative as detailedabove. In terms of their viscosities, one class of exemplary alkylsubstituted celluloses includes those whose viscosity is within therange of about 100 to about 110,000 centipoise as a 2% aqueous solutionat 20° C. Another class includes those whose viscosity is within therange of about 1,000 to about 4,000 centipoise as a 1% aqueous solutionat 20° C.

In one embodiment, the extended release polymer(s) may be a polyalkyleneoxide. In another aspect, the polyalkylene oxide may bepoly(ethylene)oxide. In a further embodiment, the poly(ethylene)oxidemay have an approximate molecular weight between 500,000 Daltons (Da) toabout 10,000,000 Da or about 900,000 Da to about 7,000,000 Da. In yet afurther embodiment, the poly(ethylene) oxide may have a molecular weightof approximately 600,000 Da, 700,000 Da, 800,000 Da, 900,000 Da,1,000,000 Da, 2,000,000 Da, 3,000,000 Da, 4,000,000 Da, 5,000,000 Da,6,000,000 Da, 7,000,000 Da, 8,000,000 Da 9,000,000 Da, or 10,000,000 Da.

In another embodiment, the polyethylene oxide may be any desirable gradeof POLYOX™ or any combination thereof. By way of example and withoutlimitation, the POLYOX™ grade may be WSR N-10, WSR N-80, WSR N-750, WSR205, WSR 1105, WSR N-12K, WSR N-60K, WSR-301, WSR Coagulant, WSR-303,WSR-308, WSR N-3000, UCARFLOC Polymer 300, UCARFLOC Polymer 302,UCARFLOC Polymer 304, and UCARFLOC Polymer 309. In one embodiment, thepolyethylene oxide may have an average molecular weight of from about100,000 Da to about 8,000,000 Da. In another embodiment, thepolyethylene oxide may have an average molecular weight of about 100,000Da, about 200,000 Da, about 300,000 Da, about 400,000 Da, about 600,000Da, about 900,000 Da, about 1,000,000 Da, about 2,000,000 Da, about4,000,000 Da, about 5,000,000 Da, about 7,000,000 Da, or about 8,000,000Da. In still another embodiment, the polyethylene oxide may have anaverage number of repeating ethylene oxide units (—CH₂CH₂O—) of about2,000 to about 160,000. In yet another embodiment, the polyethyleneoxide may have an average number of repeating ethylene oxide units ofabout 2,275, about 4,500, about 6,800, about 9,100, about 14,000, about20,000, about 23,000, about 45,000, about 90,000, about 114,000, orabout 159,000.

The release profile of the extended release pharmaceutical compositiondisclosed herein will depend partially upon the molecular weight of theextended release polymer(s). In certain embodiments, the polymers are ofa moderate to high molecular weight (900,000 Da to 4,000,000 Da) tocontrol release of oxycodone and/or acetaminophen from the compositionvia diffusion of the active agent(s) out of the polymer and/or erosionof the polymer. An example of suitable polyethylene oxide polymers arethose having molecular weights (viscosity average) on the order of about900,000 Da to about 2,000,000 Da. Using a lower molecular weight (“MW”)polyethylene oxide, such as POLYOX® 1105 (900,000 MW), the release ratesfor both drugs are higher. Using a higher molecular weight polyethyleneoxide (such as POLYOX® N-60K (2,000,000 MW) or POLYOX® WSR-301(4,000,000 MW) reduces the rate of release for both drugs. In anotherembodiment of the invention, a hydroxypropylmethylcellulose polymer ofsuch molecular weight is utilized so that the viscosity of a 2% aqueoussolution is about 4000 cps to greater than about 100,000 cps.

The release profile of the extended release pharmaceutical compositiondisclosed herein may also depend upon the amount of the extended releasepolymer(s) in the pharmaceutical composition. In general, the releaserates for oxycodone and/or acetaminophen may be decreased by increasingthe amount of the extended release polymer(s) in the pharmaceuticalcomposition. By way of example and without limitation, the releaseprofile of acetaminophen and oxycodone may be decreased by increasingthe amount of POLYOX® 1105 from about 25% by weight of the ER portion toabout 35% by weight of the ER portion.

The amount of extended release polymer or polymers present in theextended release portion(s) of the pharmaceutical composition can andwill vary. In one embodiment, the polymer present in an extended releaseportion of the pharmaceutical composition may range from about 15% toabout 70% (w/w), or about 20% to about 60% (w/w), or about 25% to about55% (w/w) of the total weight of such extended release portion of thedosage form. In another embodiment, the amount of polymer present in anextended release portion of the pharmaceutical composition may rangefrom about 30% to about 50% (w/w) of the total weight of such extendedrelease portion. In still another embodiment, the amount of polymerpresent in an extended release portion of the pharmaceutical compositionmay range from about 35% to about 45% (w/w) of the total weight of suchextended release portion. In yet another embodiment, the amount ofpolymer present in an extended release portion of the pharmaceuticalcomposition may be about 30%, 35%, 40%, 45%, 50%, 55%, or 60% (w/w) ofthe total weight of such extended release portion. In one embodiment,the amount of polymer present in an extended release portion of thepharmaceutical composition may be about 35% (w/w) of the total weight ofsuch extended release portion. In another embodiment, the amount ofpolymer present in an extended release portion of the pharmaceuticalcomposition may be about 45% (w/w) of the total weight of such extendedrelease portion. In one embodiment, the ER layer swells upon imbibitionof fluid to a size which is about 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% larger than the sizeof the ER layer prior to imbibition of fluid. In another embodiment, theER layer swells upon imbibition of fluid to a size at least about 25%larger than the size of the ER layer prior to imbibition of fluid withinabout 15 minutes of the start of fluid imbibition. In still anotherembodiment, the ER layer swells upon imbibition of fluid to a size atleast about 100% larger than the size of the ER layer prior toimbibition of fluid within about 45 min, 50 min, 60 min, 75 min, or 90min of the start of fluid imbibitions.

(iv) Excipients

The extended release portion(s) of the pharmaceutical composition mayfurther comprise at least one excipient. Suitable excipients includebinders, fillers, lubricants, antioxidants, chelating agents, and coloragents.

In one embodiment, the extended release portion(s) of the pharmaceuticalcomposition may comprise at least one binder. Suitable binders include,without limit, starches (including corn starch and pregelatinizedstarch), gelatin, sugars (including sucrose, glucose, dextrose andlactose), polyethylene glycol, polyols, polyvinylalcohols, C12-C18 fattyacid alcohols, waxes, gums (e.g., guar gum, arabic gum, acacia gum,xanthan gum, etc.), gelatin, pectin, sodium alginate,polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxylcellulose,methylcellulose, microcrystalline cellulose, ethylcellulose,hydroxyethyl cellulose, and the like), polyacrylamides, andpolyvinyloxoazolidone. In one embodiment, the amount of binder orbinders in an extended release portion of the pharmaceutical compositionmay range from about 0.5% to about 8.0% (w/w) of such extended releaseportion. In various embodiments, an extended release portion of thepharmaceutical composition may comprise at least one binder that ispresent in an amount that is about 0.5%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%,1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%,7.5%, or 8.0% (w/w) of such extended release portion of the dosage form.

In another embodiment, the extended release portion(s) of thepharmaceutical composition may comprise at least one filler. Suitablefillers include but are not limited to microcrystalline cellulose (MCC),dibasic calcium phosphate, tribasic calcium phosphate, magnesiumcarbonate, magnesium oxide, calcium silicate, magnesium aluminumsilicate, silicon dioxide, titanium dioxide, alumina, talc, kaolin,polyvinylpyrrolidone, dibasic calcium sulfate, tribasic calcium sulfate,starch, calcium carbonate, magnesium carbonate, carbohydrates, modifiedstarches, lactose, sucrose, dextrose, mannitol, sorbitol, and inorganiccompounds. In one embodiment, the amount of filler or fillers in anextended release portion may range from about 2% to about 50% (w/w) ofthe total weight of such extended release portion. In variousembodiments, an extended release portion of the pharmaceuticalcomposition may comprise at least one filler that is present in anamount that is about 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%,43%, 44%, or 45% (w/w) of such extended release portion of the dosageform.

In a further embodiment, the extended release portion(s) of thepharmaceutical composition may further comprise a lubricant. Usefullubricants include magnesium stearate, calcium stearate, stearic acid,and hydrogenated vegetable oil (preferably comprised of hydrogenated andrefined triglycerides of stearic and palmitic acids). The lubricant maybe present in an amount ranging from about 0.1% to about 3.0% (w/w) ofthe total weight of such extended release portion. In certainembodiments, the amount of lubricant in an extended release portion maybe about 0.25%, 0.5%, 0.75%, 1.0%, 1.5%, 1.75%, 1.80%, 1.85%, 1.90%, or2.0% (w/w) of the total weight of such extended release portion.

In yet another embodiment, the extended release portion(s) of thepharmaceutical composition may comprise at least one antioxidant.Suitable antioxidants include, without limit, ascorbic acid, citricacid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, and propylgallate.The amount of antioxidant present in an extended release portion of thepharmaceutical composition may range from about 0.01% to about 4.0%, orfrom about 0.02% to about 0.10% (w/w). In various embodiments, theamount of antioxidant present in an extended release portion of thepharmaceutical composition may be about 0.01%, 0.02%, 0.03%, 0.04%,0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.12%, 0.14%, 0.16%, 0.18%.0.20%, 0.25%, 0.50%, 0.75%, 1.00%, 1.50%, or 2.00% (w/w) of the totalweight of such extended release portion.

In still another embodiment, the extended release portion(s) of thepharmaceutical composition may comprise at least one chelating agent.Suitable chelating agents include ethylenediamine tetracetic acid (EDTA)and its salts, N-(hydroxy-ethyl)ethylenediaminetriacetic acid,nitrilotriacetic acid (NIA),ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,1,4,7,10-tetraazacyclodo-decane-N,N′,N″,N′″-tetraacetic acid,1,4,7,10-tetraaza-cyclododecane-N,N′,N″-triacetic acid,1,4,7-tris(carboxymethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazocyclodecane,1,4,7-triazacyclonane-N,N′,N″-triacetic acid,1,4,8,11-tetraazacyclotetra-decane-N,N′,N″,N′″-tetraacetic acid;diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,bis(aminoethanethiol)carboxylic acid, triethylenetetraamine-hexaaceticacid, and 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid. In oneembodiment, the chelating agent is the sodium salt of EDTA. The amountof chelating agent present in an extended release portion of thepharmaceutical composition may range from about 0.001% to about 0.20%(w/w) of such extended release portion. In some embodiments, the amountof chelating agent present in an extended release portion of thepharmaceutical composition may be about 0.001%, 0.002%, 0.003%, 0.004%,0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w/w) of the total weight ofsuch extended release portion.

In an alternate embodiment, the extended release portion(s) of thepharmaceutical composition may comprise a color agent. Suitable coloradditives include, but are not limited to, food, drug and cosmeticcolors (FD&C), drug and cosmetic colors (D&C), and external drug andcosmetic colors (Ext. D&C). In various embodiments, the amount of coloragent present in an extended release portion may range from about 2.0%to about 5.0% (w/w) of such extended release portion of the dosage form.In other embodiments, the amount of color agent present in an extendedrelease portion may be about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%,4.5%, or 5.0% (w/w) of such extended release portion.

(c) Dosage Forms of the Pharmaceutical Composition

The physical form of the pharmaceutical composition disclosed herein canand will vary. In general, the pharmaceutical composition is a soliddosage form comprising at least one extended release portion and,optionally, at least one immediate release portion. Suitable soliddosage forms include tablets, caplets, capsules, encapsulated beads, andgelcaps. Non-limiting types of tablets include coated tablets, uncoatedtablets, bilayer tablets, multiparticle tablets, monolithic tablets,matrix tablets, compressed tablets, and molded tablets. Non-limitingtypes of capsules include hard capsules and multi-layer capsules.

In one embodiment, the dosage form may be a capsule. Non-limitingexamples of suitable hard capsules include hard starch capsules, hardgelatin capsules, hard cellulose capsules, and hydrogel capsules. In oneexample, the core of the capsule may comprise the at least one extendedrelease portion and the shell of the capsule may comprise the at leastone immediate release portion of the composition. In another example,the core of the capsule may comprises one extended release portion,comprising oxycodone, acetaminophen and an extended release component,and the shell of the capsule may comprise one immediate release portionof the composition comprising oxycodone and acetaminophen. In yetanother example, the core of the capsule may comprise two extendedrelease portions, each comprising an extended release component and oneof oxycodone or acetaminophen, and the shell of the capsule may comprisetwo immediate release portions of the composition, each comprising oneof the oxycodone and the acetaminophen. In still another embodiment, thedosage form may be a sustained release capsule comprising the oxycodoneor the acetaminophen and exhibiting immediate release and/or extendedrelease properties.

In another embodiment, the dosage form may be a tablet comprising atleast one extended release portion and at least one immediate releaseportion. The at least one immediate release portion may be adjacent to,abutting, or surrounding the at least one extended release portion. Inone embodiment, the dosage form may be a bilayer tablet comprising oneextended release layer comprising the oxycodone and the acetaminophenand one immediate release layer comprising the oxycodone and theacetaminophen. The bilayer tablet may comprise a coating. In anotherembodiment, the dosage form may be a multilayer tablet comprising twoextended release portions, each comprising one of the oxycodone and theacetaminophen, and one immediate release portion comprising both theoxycodone and the acetaminophen. In yet another embodiment, the dosageform may be a multilayer tablet comprising two extended releaseportions, each comprising one of the oxycodone and the acetaminophen,and two immediate release portions, each comprising one of the oxycodoneand the acetaminophen. In still another embodiment, the dosage form maybe a sustained release tablet comprising the oxycodone and/oracetaminophen and exhibiting immediate release and/or extended releaseproperties.

In certain embodiments, the tablet may have a friability of no greaterthan about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.7% or 1.0%. In anotherembodiment, the tablet may have a friability of greater than 0 but lessthat about 1.0%, greater than 0 but less than about 0.5%, greater than 0but less than about 0.3%, or greater than 0 but less than about 0.2%. Instill another embodiment, the tablet may have a friability of zero.

In another embodiment, the tablet may have a hardness of at least about10 Kilopond (also known as kilopons) (kp). In some embodiments, thetablet may have a hardness of about 9 kp to about 25 kp, or about 12 kpto about 20 kp. In further embodiments, the tablet may have a hardnessof about 11 kp, 12 kp, 13 kp, 14 kp, 15 kp, 16 kp, 17 kp, 18 kp, 19 kp,or 20 kp.

In additional embodiments, the tablet may have a content uniformity offrom about 85 to about 115 percent by weight or from about 90 to about110 percent by weight, or from about 95 to about 105 percent by weight.In other embodiments, the content uniformity may have a relativestandard deviation (RSD) equal to or less than about 3.5%, 3.0%, 2.5%,2.0%, 1.5%, 1.0%, or 0.5%.

In still other embodiments, prior to administration to a patient orimmersion in fluid, the pharmaceutical composition may have (i) a lengthof approximately 18 mm, 18.01 mm, 18.02 mm, 18.03 mm, 18.04 mm, 18.05mm, 18.06 mm, 18.07 mm, 18.08 mm, 18.09 mm, 18.1 mm, 18.11 mm, 18.12 mm,18.13 mm, 18.14 mm, 18.15 mm, 18.16 mm, 18.17 mm, 18.18 mm, 18.19 mm,18.2 mm, 18.21 mm, 18.22 mm, 18.23 mm, 18.24 mm, 18.25 mm, 18.26 mm,18.27 mm, 18.28 mm, 18.29 mm, 18.3 mm, 18.31 mm, 18.32 mm, 18.33 mm,18.34 mm, 18.35 mm, 18.36 mm, 18.37 mm, 18.38 mm, 18.39 mm, 18.4 mm,18.41 mm, 18.42 mm, 18.43 mm, 18.44 mm, 18.45 mm, 18.46 mm, 18.47 mm,18.48 mm, 18.49 mm, 18.5 mm, 18.51 mm, 18.52 mm, 18.53 mm, 18.54 mm,18.55 mm, 18.56 mm, 18.57 mm, 18.58 mm, 18.59 mm, 18.6 mm, 18.61 mm,18.62 mm, 18.63 mm, 18.64 mm, 18.65 mm, 18.66 mm, 18.67 mm, 18.68 mm,18.69 mm, 18.7 mm, 18.71 mm, 18.72 mm, 18.73 mm, 18.74 mm, 18.75 mm,18.76 mm, 18.77 mm, 18.78 mm, 18.79 mm, 18.8 mm, 18.81 mm, 18.82 mm,18.83 mm, 18.84 mm, 18.85 mm, 18.86 mm, 18.87 mm, 18.88 mm, 18.89 mm,18.9 mm, 18.91 mm, 18.92 mm, 18.93 mm, 18.94 mm, 18.95 mm, 18.96 mm,18.97 mm, 18.98 mm, 18.99 mm, 19 mm, 19.01 mm, 19.02 mm, 19.03 mm, 19.04mm, 19.05 mm, 19.06 mm, 19.07 mm, 19.08 mm, 19.09 mm, 19.1 mm, 19.11 mm,19.12 mm, 19.13 mm, 19.14 mm, 19.15 mm, 19.16 mm, 19.17 mm, 19.18 mm,19.19 mm, 19.2 mm, 19.21 mm, 19.22 mm, 19.23 mm, 19.24 mm, 19.25 mm,19.26 mm, 19.27 mm, 19.28 mm, 19.29 mm, 19.3 mm, 19.31 mm, 19.32 mm,19.33 mm, 19.34 mm, 19.35 mm, 19.36 mm, 19.37 mm, 19.38 mm, 19.39 mm,19.4 mm, 19.41 mm, 19.42 mm, 19.43 mm, 19.44 mm, 19.45 mm, 19.46 mm,19.47 mm, 19.48 mm, 19.49 mm, 19.5 mm, 19.51 mm, 19.52 mm, 19.53 mm,19.54 mm, 19.55 mm, 19.56 mm, 19.57 mm, 19.58 mm, 19.59 mm 19.6 mm,19.61 mm, 19.62 mm, 19.63 mm, 19.64 mm, 19.65 mm, 19.66 mm, 19.67 mm,19.68 mm, 19.69 mm, 19.7 mm, 19.71 mm, 19.72 mm, 19.73 mm, 19.74 mm,19.75 mm, 19.76 mm, 19.77 mm, 19.78 mm, 19.79 mm, 19.8 mm, 19.81 mm,19.82 mm, 19.83 mm, 19.84 mm, 19.85 mm, 19.86 mm, 19.87 mm, 19.88 mm,19.89 mm, 19.9 mm, 19.91 mm, 19.92 mm, 19.93 mm, 19.94 mm, 19.95 mm,19.96 mm, 19.97 mm, 19.98 mm, 19.99 mm, or 20 mm as measured on themajor axis, (ii) a width of approximately 11 mm, 11.01 mm, 11.02 mm,11.03 mm, 11.04 mm, 11.05 mm, 11.06 mm, 11.07 mm, 11.08 mm, 11.09 mm,11.1 mm, 11.11 mm, 11.12 mm, 11.13 mm, 11.14 mm, 11.15 mm, 11.16 mm,11.17 mm, 11.18 mm, 11.19 mm, 11.2 mm, 11.21 mm, 11.22 mm, 11.23 mm,11.24 mm, 11.25 mm, 11.26 mm, 11.27 mm, 11.28 mm, 11.29 mm, 11.3 mm,11.31 mm, 11.32 mm, 11.33 mm, 11.34 mm, 11.35 mm, 11.36 mm, 11.37 mm,11.38 mm, 11.39 mm, 11.4 mm, 11.41 mm, 11.42 mm, 11.43 mm, 11.44 mm,11.45 mm, 11.46 mm, 11.47 mm, 11.48 mm, 11.49 mm, 11.5 mm, 11.51 mm,11.52 mm, 11.53 mm, 11.54 mm, 11.55 mm, 11.56 mm, 11.57 mm, 11.58 mm,11.59 mm, 11.6 mm, 11.61 mm, 11.62 mm, 11.63 mm, 11.64 mm, 11.65 mm,11.66 mm, 11.67 mm, 11.68 mm, 11.69 mm, 11.7 mm, 11.71 mm, 11.72 mm,11.73 mm, 11.74 mm, 11.75 mm, 11.76 mm, 11.77 mm, 11.78 mm, 11.79 mm,11.8 mm, 11.81 mm, 11.82 mm, 11.83 mm, 11.84 mm, 11.85 mm, 11.86 mm,11.87 mm, 11.88 mm, 11.89 mm, 11.9 mm, 11.91 mm, 11.92 mm, 11.93 mm,11.94 mm, 11.95 mm, 11.96 mm, 11.97 mm, 11.98 mm, 11.99 mm, 12 mm, 12.01mm, 12.02 mm, 12.03 mm, 12.04 mm, 12.05 mm, 12.06 mm, 12.07 mm, 12.08mm, 12.09 mm, 12.1 mm, 12.11 mm, 12.12 mm, 12.13 mm, 12.14 mm, 12.15 mm,12.16 mm, 12.17 mm, 12.18 mm, 12.19 mm, 12.2 mm, 12.21 mm, 12.22 mm,12.23 mm, 12.24 mm, 12.25 mm, 12.26 mm, 12.27 mm, 12.28 mm, 12.29 mm,12.3 mm, 12.31 mm, 12.32 mm, 12.33 mm, 12.34 mm, 12.35 mm, 12.36 mm,12.37 mm, 12.38 mm, 12.39 mm, 12.4 mm, 12.41 mm, 12.42 mm, 12.43 mm,12.44 mm, 12.45 mm, 12.46 mm, 12.47 mm, 12.48 mm, 12.49 mm, 12.5 mm,12.51 mm, 12.52 mm, 12.53 mm, 12.54 mm, 12.55 mm, 12.56 mm, 12.57 mm,12.58 mm, 12.59 mm, 12.6 mm, 12.61 mm, 12.62 mm, 12.63 mm, 12.64 mm,12.65 mm, 12.66 mm, 12.67 mm, 12.68 mm, 12.69 mm, 12.7 mm, 12.71 mm,12.72 mm, 12.73 mm, 12.74 mm, 12.75 mm, 12.76 mm, 12.77 mm, 12.78 mm,12.79 mm, 12.8 mm, 12.81 mm, 12.82 mm, 12.83 mm, 12.84 mm, 12.85 mm,12.86 mm, 12.87 mm, 12.88 mm, 12.89 mm, 12.9 mm, 12.91 mm, 12.92 mm,12.93 mm, 12.94 mm, 12.95 mm, 12.96 mm, 12.97 mm, 12.98 mm, 12.99 mm, or13 mm, and (iii) a height or thickness of approximately 5 mm, 5.01 mm,5.02 mm, 5.03 mm, 5.04 mm, 5.05 mm, 5.06 mm, 5.07 mm, 5.08 mm, 5.09 mm,5.1 mm, 5.11 mm, 5.12 mm, 5.13 mm, 5.14 mm, 5.15 mm, 5.16 mm, 5.17 mm,5.18 mm, 5.19 mm, 5.2 mm, 5.21 mm, 5.22 mm, 5.23 mm, 5.24 mm, 5.25 mm,5.26 mm, 5.27 mm, 5.28 mm, 5.29 mm, 5.3 mm, 5.31 mm, 5.32 mm, 5.33 mm,5.34 mm, 5.35 mm, 5.36 mm, 5.37 mm, 5.38 mm, 5.39 mm, 5.4 mm, 5.41 mm,5.42 mm, 5.43 mm, 5.44 mm, 5.45 mm, 5.46 mm, 5.47 mm, 5.48 mm, 5.49 mm,5.5 mm, 5.51 mm, 5.52 mm, 5.53 mm, 5.54 mm, 5.55 mm, 5.56 mm, 5.57 mm,5.58 mm, 5.59 mm, 5.6 mm, 5.61 mm, 5.62 mm, 5.63 mm, 5.64 mm, 5.65 mm,5.66 mm, 5.67 mm, 5.68 mm, 5.69 mm, 5.7 mm, 5.71 mm, 5.72 mm, 5.73 mm,5.74 mm, 5.75 mm, 5.76 mm, 5.77 mm, 5.78 mm, 5.79 mm, 5.8 mm, 5.81 mm,5.82 mm, 5.83 mm, 5.84 mm, 5.85 mm, 5.86 mm, 5.87 mm, 5.88 mm, 5.89 mm,5.9 mm, 5.91 mm, 5.92 mm, 5.93 mm, 5.94 mm, 5.95 mm, 5.96 mm, 5.97 mm,5.98 mm, 5.99 mm, or 6 mm. In yet another embodiment, the pharmaceuticalcomposition may have (i) a length of approximately 19.1 mm, 19.11 mm,19.12 mm, 19.13 mm, 19.14 mm, 19.15 mm, 19.16 mm, 19.17 mm, 19.18 mm,19.19 mm, 19.2 mm, 19.21 mm, 19.22 mm, 19.23 mm, 19.24 mm, 19.25 mm,19.26 mm, 19.27 mm, 19.28 mm, 19.29 mm, or 19.3 mm as measured on themajor axis, (ii) a width of approximately 12.4 mm, 12.41 mm, 12.42 mm,12.43 mm, 12.44 mm, 12.45 mm, 12.46 mm, 12.47 mm, 12.48 mm, 12.49 mm, or12.5 mm, and (iii) a height or thickness of approximately 5.6 mm, 5.61mm, 5.62 mm, 5.63 mm, 5.64 mm, 5.65 mm, 5.66 mm, 5.67 mm, 5.68 mm, 5.69mm, 5.7 mm, 5.71 mm, 5.72 mm, 5.73 mm, 5.74 mm, 5.75 mm, 5.76 mm, 5.77mm, 5.78 mm, 5.79 mm, or 5.8 mm.

In additional embodiments, the pharmaceutical composition may expandupon immersion in fluid to have (i) a length of about 18.5 mm, 18.6 mm,18.7 mm, 18.8 mm, 18.9 mm, 19 mm, 19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm,19.5 mm, 19.6 mm, 19.7 mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm,20.3 mm, 20.4 mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, or 21 mm;and (ii) a width of about 11 mm, 11.1 mm, 11.2 mm, 11.3 mm, 11.4 mm,11.5 mm, 11.6 mm, 11.7 mm, 11.8 mm, 11.9 mm, 12 mm, 12.1 mm, 12.2 mm,12.3 mm, 12.4 mm, 12.5 mm, 12.6 mm, 12.7 mm, 12.8 mm, 12.9 mm, 13 mm,13.1 mm, 13.2 mm, 13.3 mm, 13.4 mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm,13.9 mm, or 14 mm within about 5 minutes of immersion in fluid. In otherembodiments, the pharmaceutical composition may expand upon immersion influid to (i) a length of about 18.5 mm, 18.6 mm, 18.7 mm, 18.8 mm, 18.9mm, 19 mm, 19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm, 19.7mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4 mm, 20.5mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm, 21.2 mm, 21.3mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9 mm, or 22 mm; and(ii) a width of about 11 mm, 11.1 mm, 11.2 mm, 11.3 mm, 11.4 mm, 11.5mm, 11.6 mm, 11.7 mm, 11.8 mm, 11.9 mm, 12 mm, 12.1 mm, 12.2 mm, 12.3mm, 12.4 mm, 12.5 mm, 12.6 mm, 12.7 mm, 12.8 mm, 12.9 mm, 13 mm, 13.1mm, 13.2 mm, 13.3 mm, 13.4 mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9mm, 14 mm, 14.1 mm, 14.2 mm, 14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7mm, 14.8 mm, 14.9 mm, or 15 mm within about 10 minutes to about 15minutes of immersion in fluid. In still other embodiments, thepharmaceutical composition may expand upon immersion in fluid to (i) alength of about 19 mm, 19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm, 19.6mm, 19.7 mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm, 20.4mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm, 21.2mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9 mm, 22mm, 22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm, or 22.5 mm; and (ii) a width ofabout 12 mm, 12.1 mm, 12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm, 12.6 mm, 12.7mm, 12.8 mm, 12.9 mm, 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4 mm, 13.5mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm, 14.2 mm, 14.3mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9 mm, or 15 mmwithin about 20 minutes to about 25 minutes of immersion in fluid. Inadditional embodiments, the pharmaceutical composition may expand uponimmersion in fluid to (i) a length of about 19 mm, 19.1 mm, 19.2 mm,19.3 mm, 19.4 mm, 19.5 mm, 19.6 mm, 19.7 mm, 19.8 mm, 19.9 mm, 20 mm,20.1 mm, 20.2 mm, 20.3 mm, 20.4 mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm,20.9 mm, 21 mm, 21.1 mm, 21.2 mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm,21.7 mm, 21.8 mm, 21.9 mm, 22 mm, 22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm,22.5 mm, 22.6 mm, 22.7 mm, 22.8 mm, 22.9 mm, or 23 mm; and (ii) a widthof about 12.5 mm, 12.6 mm, 12.7 mm, 12.8 mm, 12.9 mm, 13 mm, 13.1 mm,13.2 mm, 13.3 mm, 13.4 mm, 13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm,14 mm, \14.1 mm, 14.2 mm, 14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm,14.8 mm, 14.9 mm, or 15 mm within about 30 minutes to about 35 minutesof immersion in fluid. In still other embodiments, the pharmaceuticalcomposition may expand upon immersion in fluid to (i) a length of about18 mm, 18.1 mm, 18.2 mm, 18.3 mm, 18.4 mm, 18.5 mm, 18.6 mm, 18.7 mm,18.8 mm, 18.9 mm, 19 mm, 19.1 mm, 19.2 mm, 19.3 mm, 19.4 mm, 19.5 mm,19.6 mm, 19.7 mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm, 20.3 mm,20.4 mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm, 21.1 mm,21.2 mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm, 21.9 mm,22 mm, 22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm, 22.5 mm, 22.6 mm, 22.7 mm,22.8 mm, 22.9 mm, 23 mm, 23.1 mm, 23.2 mm, 23.3 mm, 23.4 mm, or 23.5;(ii) a width of about 11.5 mm, 11.6 mm, 11.7 mm, 11.8 mm, 11.9 mm, 12mm, 12.1 mm, 12.2 mm, 12.3 mm, 12.4 mm, 12.5 mm, 12.6 mm, 12.7 mm, 12.8mm, 12.9 mm, 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4 mm, 13.5 mm, 13.6mm, 13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm, 14.2 mm, 14.3 mm, 14.4mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9 mm, 15 mm, 15.1 mm, 15.2mm, 15.3 mm, 15.4 mm, 15.5 mm, 15.6 mm, 15.7 mm, 15.8 mm, 15.9 mm, or 16mm; and (iii) a height or thickness of about 5.5 mm, 5.6 mm, 5.7 mm, 5.8mm, 5.9 mm, 6 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7mm, 6.8 mm, 6.9 mm, or 7 mm within about 50 minutes to about 55 minutesof immersion in fluid. In yet another embodiment, the pharmaceuticalcomposition may expand upon immersion in fluid to (i) a length of about19.5 mm, 19.6 mm, 19.7 mm, 19.8 mm, 19.9 mm, 20 mm, 20.1 mm, 20.2 mm,20.3 mm, 20.4 mm, 20.5 mm, 20.6 mm, 20.7 mm, 20.8 mm, 20.9 mm, 21 mm,21.1 mm, 21.2 mm, 21.3 mm, 21.4 mm, 21.5 mm, 21.6 mm, 21.7 mm, 21.8 mm,21.9 mm, 22 mm, 22.1 mm, 22.2 mm, 22.3 mm, 22.4 mm, 22.5 mm, 22.6 mm,22.7 mm, 22.8 mm, 22.9 mm, 23 mm, 23.1 mm, 23.2 mm, 23.3 mm, 23.4 mm, or23.5; (ii) a width of about 13 mm, 13.1 mm, 13.2 mm, 13.3 mm, 13.4 mm,13.5 mm, 13.6 mm, 13.7 mm, 13.8 mm, 13.9 mm, 14 mm, 14.1 mm, 14.2 mm,14.3 mm, 14.4 mm, 14.5 mm, 14.6 mm, 14.7 mm, 14.8 mm, 14.9 mm, 15 mm,15.1 mm, 15.2 mm, 15.3 mm, 15.4 mm, 15.5 mm, 15.6 mm, 15.7 mm, 15.8 mm,15.9 mm, or 16 mm; and (iii) a height or thickness of about 5.5 mm, 5.6mm, 5.7 mm, 5.8 mm, 5.9 mm, 6 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, or 7 mm within about 60 minutes ofimmersion in fluid.

In yet another embodiment, the length of the pharmaceutical compositionincreases by about 4%, 4.25%, 4.5% 4.75%, 5%, 5.25%, 5.5%, 5.75%, 6%,6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75% 8%, 8.25%, 8.5%, 8.75%, 9%,9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,11.75%, 12%, 12.25%, 12.5%, 12.75%, or 13% within about 10 minutes ofimmersion in fluid. In still another embodiment, the length of thepharmaceutical composition increases by about 5%, 5.25%, 5.5%, 5.75%,6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%,9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%,14.25%, 14.5%, 14.75%, or 15% within about 15 minutes of immersion influid. In yet another embodiment, the length of the pharmaceuticalcomposition increases by about 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%, 6.5%,6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%,9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%,12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,14.75%, or 15% within about 20 minutes of immersion in fluid. In afurther embodiment, the length of the pharmaceutical compositionincreases by about 7%, 7.25%, 7.5%, 7.75% 8%, 8.25%, 8.5%, 8.75%, 9%,9.25% 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%,14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%,16.75%, 17%, 17.25%, 17.5%, 17.75%, or 18% within about 30 minutes ofimmersion in fluid. In another embodiment, the length of thepharmaceutical composition increases by about 8%, 8.25%, 8.5%, 8.75%,9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%,11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%,14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%,16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%, 18.25%, 18.5%, 18.75%, or 19%within about 45 minutes of immersion in fluid. In yet anotherembodiment, the length of the pharmaceutical composition increases byabout 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25% 9.5%, 9.75%, 10%, 10.25%, 10.5%,10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%,13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%,15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%,18.25%, 18.5%, 18.75%, or 19% within about 55 minutes of immersion influid. In still another embodiment, the length of the pharmaceuticalcomposition increases by about 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%,9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%,12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%,17.25%, 17.5%, 17.75%, 18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%,19.75%, or 20% within about 60 minutes of immersion in fluid.

In a further embodiment, the width of the pharmaceutical compositionincreases by about 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%,8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%,11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%,13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%, or 15% within about 10minutes of immersion in fluid. In still another embodiment, the width ofthe pharmaceutical composition increases by about 6%, 6.25%, 6.5%,6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%,9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%,12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%,17.25%, 17.5%, 17.75%, or 18%, within about 15 minutes of immersion influid. In yet another embodiment, the width of the pharmaceuticalcomposition increases by about 6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%,7.75%, 8%, 8.25%, 8.5%, 8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%,10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%, 12.75%,13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%,15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%,or 18%, within about 20 minutes of immersion in fluid. In a furtherembodiment, the width of the pharmaceutical composition increases byabout 10%, 10.25%, 10.5%, 10.75%, 11%, 11.25%, 11.5%, 11.75%, 12%,12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%,14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%,17.25%, 17.5%, 17.75%, 18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%,19.75%, 20%, 20.25%, 20.5%, 20.75%, 21%, 21.25%, 21.5%, 21.75%, 22%,22.25%, 22.5%, 22.75%, 23%, 23.25%, 23.5%, 23.75%, or 24% within about30 minutes of immersion in fluid. In another embodiment, the width ofthe pharmaceutical composition increases by about 12%, 12.25%, 12.5%,12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%, 15%,15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%,17.75%, 18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, 20%,20.25%, 20.5%, 20.75%, 21%, 21.25%, 21.5%, 21.75%, 22%, 22.25%, 22.5%,22.75%, 23%, 23.25%, 23.5%, 23.75%, 24%, 24.25%, 24.5%, 24.75%, or 25%within about 45 minutes of immersion in fluid. In yet anotherembodiment, the width of the pharmaceutical composition increases byabout 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%, 13.5%, 13.75%, 14%,14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%, 15.75%, 16%, 16.25%, 16.5%,16.75%, 17%, 17.25%, 17.5%, 17.75%, 18%, 18.25%, 18.5%, 18.75%, 19%,19.25%, 19.5%, 19.75%, 20.25%, 20.5%, 20.75%, 21%, 21.25%, 21.5%,21.75%, 22%, 22.25%, 22.5%, 22.75%, 23%, 23.25%, 23.5%, 23.75%, 24%,24.25%, 24.5%, 24.75%, or 25% within about 55 minutes of immersion influid. In still another embodiment, the width of the pharmaceuticalcomposition increases by about 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%,15.5%, 15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%,18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, 20%, 20.25%,20.5%, 20.75%, 21%, 21.25%, 21.5%, 21.75%, 22%, 22.25%, 22.5%, 22.75%,23%, 23.25%, 23.5%, 23.75%, 24%, 24.25%, 24.5%, 24.75%, 25%, 25.25%,25.5%, 25.75%, or 26% within about 60 minutes of immersion in fluid.

The pharmaceutical composition disclosed herein includes one or moredosage forms that are designed to achieve the therapeutic concentrationsof the active ingredients. In some embodiments, therefore, atherapeutically effective dose of the pharmaceutical composition maycomprise one dosage form. In other embodiments, a therapeuticallyeffective dose of the pharmaceutical composition may comprise two dosageforms. In additional embodiments, a therapeutically effective dose ofthe pharmaceutical composition may comprise three or more dosage forms.

(d) Abuse and Tamper Resistant Properties of the Composition

Extended release pain medications have provided many benefits topatients in the management of their chronic pain by providing asustained release over time of a larger quantity of drug than istypically contained in an immediate release formulation. Consequently,these dosage forms (especially if they contain opioids) are attractivetargets for drug abusers looking to defeat the extended releaseformulation to allow immediate bolus administration or “dose-dumping” ofthe entire drug contents of the dosage form.

Dosage forms of the pharmaceutical composition disclosed herein may bemore resistant to crushing, grinding, pulverizing, or other common meansused to produce a powder than an immediate release product. Accordingly,some embodiment forms are tamper resistant and less prone to abuse ormisuse. For example, certain embodiments may not be crushed into apowder and snorted. Additionally, some embodiments comprising anextended release polymer may not be crushed, mixed with an aqueoussolution, and injected (i.e., the resultant mixture becomes extremelyviscous and cannot be drawn into a syringe.

For example, dosage forms of the pharmaceutical composition disclosedherein form a pasty semi-solid mixture when dissolved. Thus, thepharmaceutical composition is difficult to draw into a syringe andinject intravenously. The yield of active pharmaceutical ingredient(s)obtained from the pharmaceutical composition is also low (less than20%).

Further, dosage forms of the pharmaceutical composition disclosed hereincannot easily be snorted. In order for a drug abuser to successfullysnort a drug obtained from a dosage form, he must prepare a crushed,finely divided powder form of the dosage form for insufflating thepowder into the nasal cavity. However, the pharmaceutical compositionsdisclosed herein form a clumpy, solid mass and do not allow acceptableabsorption through the nasal tissue.

Dosage forms of the pharmaceutical composition disclosed herein also donot allow “dose dumping” caused by the deliberate introduction ofalcohol into a drug abuser's stomach which accelerates the release ofactive ingredient(s) from the time-release formulation. Thepharmaceutical compositions disclosed herein are resistant to theaccelerated release of active ingredient(s).

In addition, dosage forms of the pharmaceutical composition disclosedherein do not allow for “free basing.” Successful free basing by a drugabuser requires the generation of a salt free form of the activepharmaceutical ingredient(s). This requires physical and chemicalmanipulation to release the active pharmaceutical ingredient(s) from itssalt(s) and selective extraction from other matrix excipients. Thepharmaceutical composition disclosed herein cannot be easily manipulatedto generate a free base preparation.

Moreover, the tamper resistance properties of the pharmaceuticalcompositions disclosed herein may be increased by increasing the averagemolecular weight of the extended release polymer used in thepharmaceutical composition. In another embodiment, the tamper resistanceproperties of the pharmaceutical compositions disclosed herein may beincreased by increasing the amount of the extended release polymer usedin the pharmaceutical composition.

In further embodiments, the solid oral dosage forms of thepharmaceutical compositions disclosed herein exhibit substantialdifferences in the release profiles of oxycodone and acetaminophen whenthe dosage forms are crushed or ground. Indeed, the intact solid oraldosage forms surprisingly exhibit a higher release rate of both activeingredients than one that is crushed or ground. This suggests that upongrinding or crushing the solid oral dosage forms disclosed herein, theimmediate release portion and extended release portion of the dosageform combine, and the hydration and swelling of the polymer(s) in theextended release portion of the dosage form retards the release of theoxycodone and acetaminophen in the immediate release portion. Hence theincorporation of the ground or crushed components from the immediaterelease portion into a mixture with the ground or crushed components ofthe extended release portion causes the pharmaceutical composition tolose its immediate release characteristics. This feature may effectivelynegate a drug abuser's purpose for crushing the solid oral dosage formin the first place—to obtain an early onset of analgesia. Thus, this isan unexpected tamper resistant property of the pharmaceuticalcompositions disclosed herein.

In another embodiment, as the amount of oxycodone in the pharmaceuticalcomposition increases, so does the duration of gastric retention afteradministration to a subject. Consequently, if a subject eitherintentionally or accidentally ingests a larger dose of thepharmaceutical composition than prescribed, the pharmaceuticalcomposition will be retained in the stomach for a longer time periodthan an IR or traditional ER pharmaceutical composition, thereby givinga medical provider additional time to perform gastric lavage, inducevomiting, or administer activated charcoal to prevent the body fromabsorbing the oxycodone. In a further embodiment, the pharmaceuticalcomposition provides a medical provider with about an additional 15minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105minutes, 2.0 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3.0 hours, 3.25hours, 3.5 hours, 3.75 hours, or 4 hours in which to prevent theabsorption of oxycodone in the subject. In another embodiment, thepharmaceutical composition provides a medical provider with sufficienttime to treat a subject who has overdosed on oxycodone so that death,difficulty breathing, cardiac arrest, and limp muscles do not occur inthe subject.

In yet another embodiment, if vomiting is induced or naturally occurs asa result of an increased dose of oxycodone, the entire pharmaceuticalcomposition is expelled from the subject. Thus, toxic concentrations ofthe oxycodone due to absorption into the subject's blood are preventedby removing the further release of oxycodone. In still anotherembodiment, if vomiting is induced or naturally occurs as a result ofthe increased dose of oxycodone about 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99%, or 100% of the pharmaceutical composition isexpelled from the subject. In yet another embodiment, if vomiting isinduced or naturally occurs within about 30 minutes to about 60 minutesafter ingestion of the increased dose of oxycodone about 50% to about65% of the oxycodone dose is expelled from the subject.

(e) In Vitro Release Properties of the Composition

The in vitro release rates of oxycodone and acetaminophen from thepharmaceutical compositions disclosed herein may be measured in 900 mLof 0.1 N HCl using a USP type II paddle apparatus and at a paddle speedof either about 100 rpm or 150 rpm and a constant temperature of 37° C.

In one embodiment, the at least one immediate release portion of thecomposition may have in vitro release rates of oxycodone andacetaminophen as follows: more than about 90% of the oxycodone and/orthe acetaminophen present in the at least one immediate release portionmay be released within about 15 minutes, or essentially 100% of theoxycodone and/or the acetaminophen present in the at least one immediaterelease portion may be released within about 15 minutes. In anotherembodiment, more than about 90% of the oxycodone and/or theacetaminophen present in the at least one immediate release portion maybe released within about 5 minutes. In yet another embodiment,essentially 100% of the oxycodone and/or acetaminophen present in the atleast one immediate release portion may be released within about 5minutes.

In one embodiment, the at least one extended release portion of thecomposition may have in vitro release rates of oxycodone as follows:from about 1% to about 20% of the oxycodone present in the at least oneextended release portion may be released within about 15 minutes, fromabout 35% to about 55% of the oxycodone present in the at least oneextended release portion may be released within about 2 hours, fromabout 65% to about 85% of the oxycodone present in the at least oneextended release portion may be released within about 4 hours, and atleast about 90% of the oxycodone present in the at least one extendedrelease portion may be released within about 8 hours.

In yet another embodiment, the at least one extended release portion mayhave in vitro release rates of oxycodone as follows: from about 1% toabout 10% of the oxycodone present in the at least one extended releaseportion may be released within about 15 minutes, from about 40% to about50% of the oxycodone present in the at least one extended releaseportion may be released within about 2 hours, from about 70% to about80% of the oxycodone present in the at least one extended releaseportion may be released within about 4 hours, and from about 90% toabout 100% of the oxycodone present in the at least one extended releaseportion may be released within about 8 hours.

In one embodiment, the at least one extended release portion may have invitro release rates of acetaminophen as follows: from about 1% to about15% of the acetaminophen present in the at least one extended releaseportion may be released within about 15 minutes, from about 25% to about40% of the acetaminophen present in the at least one extended releaseportion may be released within about 2 hours, from about 50% to about65% of the acetaminophen present in the at least one extended releaseportion may be released within about 4 hours, and from about 80% toabout 95% of the acetaminophen present in the at least one extendedrelease portion may be released within about 8 hours.

In another embodiment, the at least one extended release portion of thecomposition may have in vitro release rates of acetaminophen as follows:from about 1% to about 5% of the acetaminophen present in the at leastone extended release portion may be released within about 15 minutes,from about 25% to about 35% of the acetaminophen present in the at leastone extended release portion may be released within about 2 hours, fromabout 55% to about 65% of the acetaminophen present in the at least oneextended release portion may be released within about 4 hours, and fromabout 80% to about 90% of the acetaminophen present in the at least oneextended release portion may be released within about 8 hours.

In one embodiment, the in vitro release rates of oxycodone from thecomposition may be as follows: about 25% to about 35% of oxycodone maybe released from the composition within about 15 minutes, from about 50%to about 65% of oxycodone may be released from the composition in about2 hours, from about 70% to about 85% of oxycodone may be released fromthe composition within about 4 hours, and from about 90% to about 100%of oxycodone may be released from the composition within about 8 hours.

In another embodiment, the pharmaceutical composition disclosed hereinmay have in vitro release rates of oxycodone as follows: about 25% toabout 30% of oxycodone may be released from the pharmaceuticalcomposition within about 15 minutes, from about 50% to about 60% ofoxycodone may be released from the pharmaceutical composition withinabout 2 hours, from about 70% to about 80% of oxycodone may be releasedfrom the pharmaceutical composition within about 4 hours, and from about90% to about 95% of oxycodone may be released from the pharmaceuticalcomposition within about 8 hours.

In one embodiment, the in vitro release rates of acetaminophen from thecomposition may be as follows: from about 50% to about 55% ofacetaminophen may be released from the composition in about 15 minutes,from about 60% to about 75% of acetaminophen may be released from thecomposition in about 2 hours, from about 75% to about 85% ofacetaminophen may be released from the composition in about 4 hours, andfrom about 90% to about 100% of acetaminophen may be released from thecomposition in about 8 hours.

In another embodiment, the in vitro release rates of acetaminophen fromthe pharmaceutical composition disclosed herein may be as follows: fromabout 50% to about 55% of acetaminophen may be released from thepharmaceutical composition within about 15 minutes, from about 60% toabout 70% of acetaminophen may be released from the pharmaceuticalcomposition within about 2 hours, from about 75% to about 85% ofacetaminophen may be released from the pharmaceutical composition withinabout 4 hours, and from about 90% to about 100% of acetaminophen may bereleased from the pharmaceutical composition within about 8 hours.

Additionally, the in vitro release rates of oxycodone and acetaminophenfrom the pharmaceutical composition generally are not affected by lowconcentrations of ethanol (i.e., from about 5% v/v to about 20% v/v)when measured in 900 mL of 0.1 N HCl containing the desired percentageof ethanol using a USP type II paddle apparatus and at a paddle speed ofabout 150 rpm and a constant temperature of 37° C. For example, fromabout 25% to about 35% of oxycodone and about 50% to about 55% ofacetaminophen may be released from the pharmaceutical composition withinabout 15 minutes when measured in the presence of 5% to 20% ethanol, andfrom about 50% to about 65% of oxycodone and from about 60% to about 70%of acetaminophen may be released from the pharmaceutical compositionwithin about 2 hour when measured in the presence of 5% to 20% ethanol.

The in vitro release rates of oxycodone and acetaminophen from thepharmaceutical compositions disclosed herein generally are reduced,however, in the presence of 40% ethanol. For example, from about 5% toabout 15% of the oxycodone and from about 15% to about 25% of theacetaminophen may be released from the pharmaceutical composition withinabout 15 minutes when measured in the presence of 40% ethanol, and fromabout 35% to about 45% of oxycodone and from about 45% to about 55% ofacetaminophen may be released from the pharmaceutical composition withinabout 2 hours when measured in the presence of 40% ethanol.

Stated another way, less oxycodone is extracted from the pharmaceuticalcomposition by a solution of 0.1 N HCl and 40% ethanol than is extractedby a solution of 0.1 N HCl. In some embodiments, less than about 75% ofthe oxycodone that is released in the presence of 0.1N HCl may bereleased in the presence of 0.1N HCl containing 40% ethanol. Inadditional embodiments, less than about 70%, 65%, 60%, 55%, 50%, 45%, or40% of the oxycodone that may be released in the presence of 0.1N HClmay be released in the presence of 0.1N HCl and 40% ethanol. Forexample, less than about 40% of the oxycodone that may be released inthe presence of 0.1N HCl in about 15 minutes may be released in thepresence of 0.1N HCl and 40% ethanol within about 15 minutes. In otherembodiments, less than about 60% of the oxycodone that may be releasedin the presence of 0.1N HCl in about 30 minutes may be released in thepresence of 0.1N HCl and 40% ethanol within about 30 minutes. Inadditional embodiments, less than about 75% of the oxycodone that may bereleased in the presence of 0.1N HCl in about 2 hours may be released inthe presence of 0.1N HCl and 40% ethanol within about 2 hours.

(f) Stability Data for the Pharmaceutical Composition

In one embodiment, p-aminophenol may be present in the pharmaceuticalcomposition as a degradation product of acetaminophen in any amount upto and including, but no more than, about 100 ppm. In other embodiments,p-aminophenol may be present in the pharmaceutical composition as adegradation product of acetaminophen in an amount of about 0.2 ppm toabout 6.0 ppm after storage for about 1, 2, or 3 months at a temperatureof about 25° C. to about 40° C. and at about 60% to about 75% relativehumidity. In yet another embodiment, p-aminophenol may be present in thepharmaceutical composition as a degradation product of acetaminophen inan amount of about 0.6 ppm to about 6.0 ppm after storage for about 1,2, or 3 months at a temperature of about 25° C. to about 40° C. and atabout 60% to about 75% relative humidity. In still another embodiment,p-aminophenol may be present in the pharmaceutical composition as adegradation product of acetaminophen in an amount of about 0.2 ppm, 0.3ppm, 0.4 ppm, 0.5 ppm, 0.6 ppm, 0.7 ppm, 0.8 ppm, 0.9 ppm, 1.0 ppm, 1.1ppm, 1.2 ppm, 1.3 ppm, 1.4 ppm, 1.5 ppm, 1.6 ppm, 1.7 ppm, 1.8 ppm, 1.9ppm, 2.0 ppm, 2.1 ppm, 2.2 ppm, 2.3 ppm, 2.4 ppm, 2.5 ppm, 2.6 ppm, 2.7ppm, 2.8 ppm, 2.9 ppm, 3.0 ppm, 3.1 ppm, 3.2 ppm, 3.3 ppm, 3.4 ppm, 3.5ppm, 3.6 ppm, 3.7 ppm, 3.8 ppm, 3.9 ppm, 4.0 ppm, 4.1 ppm, 4.2 ppm, 4.3ppm, 4.4 ppm, 4.5 ppm, 4.6 ppm, 4.7 ppm, 4.8 ppm, 4.9 ppm, 5.0 ppm, 5.1ppm, 5.2 ppm, 5.3 ppm, 5.4 ppm, 5.5 ppm, 5.6 ppm, 5.7 ppm, 5.8 ppm, 5.9ppm, and 6.0 ppm after storage for about 1, 2, or 3 months at atemperature of 25° C. to about 40° C. and at about 60% to about 75%relative humidity

In one embodiment, oxycodone N-oxide may be present in thepharmaceutical composition as a degradation product of oxycodone in anyamount up to and including about 0.5% by weight of the oxycodone. Inother embodiments, oxycodone N-oxide may be present in thepharmaceutical composition as a degradation product of oxycodone in anamount of about 0.01% to about 0.5% by weight of the oxycodone afterstorage for about 1, 2, or 3 months at a constant temperature of about25° C. to 4° C. and at about 60% to 75% relative humidity. In yetanother embodiment, oxycodone N-oxide may be present in thepharmaceutical composition as a degradation product of oxycodone in anamount of about 0.05% to about 0.5% by weight of the oxycodone afterstorage for about 1, 2, or 3 months at a constant temperature of about25° C. to 40° C. and at about 60% to 75% relative humidity. Inadditional embodiments, oxycodone N-oxide may be present in thepharmaceutical composition as a degradation product of oxycodone in anamount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%,0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%,0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%,0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%,0.49%, and 0.5% by weight of the oxycodone after storage for about 1, 2,or 3 months at a constant temperature of about 25° C. to about 40° C.and at about 60% to about 75% relative humidity.

In one embodiment, Related Substance A (i.e.,C-Normorphinan-6-carboxylic acid,4,5-epoxy-6,14-dihydroxy-3-methoxy-17-methyl-, (5α,6α)-) may be presentin the pharmaceutical composition as a degradation product of oxycodonein a maximum amount of about 0.5% by weight of the oxycodone. In otherembodiments, Related Substance A may be present in the pharmaceuticalcomposition as a degradation product of oxycodone in an amount of about0.01% to about 0.5% by weight of the oxycodone after storage for about1, 2, or 3 months at a temperature of about 25° C. to about 40° C. andat about 60% to about 75% relative humidity. In yet another embodiment,Related Substance A may be present in the pharmaceutical composition asa degradation product of oxycodone in an amount of about 0.05% to about0.5% by weight of the oxycodone after storage for about 1, 2, or 3months at a temperature of about 25° C. to about 40° C. and at about 60%to about 75% relative humidity. In other embodiments, Related SubstanceA may be present in the pharmaceutical composition as a degradationproduct of oxycodone in an amount of about 0.01%, 0.02%, 0.03%, 0.04%,0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%,0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%,0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%,0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%,0.45%, 0.46%, 0.47%, 0.48%, 0.49%, and 0.5% by weight of the oxycodoneafter storage for about 1, 2, or 3 months at a temperature of about 25°C. to about 40° C. and at about 60% to about 75% relative humidity.

In one embodiment, each unspecified acetaminophen degradation productmay be present in the pharmaceutical composition in any amount up toabout 0.15% by weight of the acetaminophen. In another embodiment, eachunspecified acetaminophen degradation product may be present in thepharmaceutical composition as a degradation product of acetaminophen inan amount of about 0.01% and about 0.15% by weight of the acetaminophenafter storage for about 1, 2, or 3 months at a temperature of about 25°C. to about 40° C. and at about 60% to about 75% relative humidity. Instill another embodiment, each unspecified acetaminophen degradationproduct may be present in the pharmaceutical composition as adegradation product of acetaminophen in an amount of about 0.05% andabout 0.15% by weight of the acetaminophen after storage for about 1, 2,or 3 months at a temperature of about 25° C. to about 40° C. and atabout 60% to about 75% relative humidity. In other embodiments, eachunspecified acetaminophen degradation product may be present in thepharmaceutical composition as a degradation product of acetaminophen inan amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%,0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, and 0.15% by weight ofthe acetaminophen after storage for about 1, 2, or 3 months at atemperature of about 25° C. to about 40° C. and at about 60% to about75% relative humidity.

In one embodiment, each unspecified oxycodone HCl degradation productmay be present in the pharmaceutical composition in a maximum amount ofabout 0.2% by weight of the oxycodone. In other embodiments, eachunspecified oxycodone HCl degradation product may be present in thepharmaceutical composition in an amount of about 0.01% to about 0.2% byweight of the oxycodone after storage for about 1, 2, or 3 months at atemperature of about 25° C. to about 40° C. and at about 60% to about75% relative humidity. In yet another embodiment, each unspecifiedoxycodone HCl degradation product may be present in the pharmaceuticalcomposition in an amount of about 0.05% to about 0.2% by weight of theoxycodone after storage for about 1, 2, or 3 months at a temperature ofabout 25° C. to about 40° C. and at about 60% to about 75% relativehumidity. In further embodiments, each unspecified oxycodone HCldegradation product may be present in the pharmaceutical composition inan amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%,0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%,0.18%, 0.19%, and 0.2% by weight of the oxycodone after storage forabout 1, 2, or 3 months at a temperature of about 25° C. to about 40° C.and at about 60% to about 75% relative humidity.

In one embodiment, the total acetaminophen degradation products may bepresent in the pharmaceutical composition in a maximum amount of about1.0% by weight of the acetaminophen. In other embodiments, the totalacetaminophen degradation products may be present in the pharmaceuticalcomposition in an amount of about 0.05% to about 1.0% by weight of theacetaminophen after storage for about 1, 2, or 3 months at a temperatureof about 25° C. to about 40° C. and at about 60% to about 75% relativehumidity. In further embodiments, the total acetaminophen degradationproducts may be present in the pharmaceutical composition in an amountof about 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, and1.0% by weight of the acetaminophen after storage for about 1, 2, or 3months at a temperature of about 25° C. to about 40° C. and at about 60%to about 75% relative humidity.

In one embodiment, the total oxycodone degradation products may bepresent in the pharmaceutical composition in a maximum amount of about1.0% by weight of the oxycodone. In further embodiments, the totaloxycodone degradation products may be present in the pharmaceuticalcomposition in an amount of about 0.05% to about 1.0% by weight of theoxycodone after storage for about 1, 2, or 3 months at a temperature ofabout 25° C. to about 40° C. and at about 60% to about 75% relativehumidity. In yet other embodiments, the total oxycodone degradationproducts may be present in the pharmaceutical composition in an amountof about 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, and1.0% by weight of the oxycodone after storage for about 1, 2, or 3months at a temperature of about 25° C. to about 40° C. and at about 60%to about 75% relative humidity.

(g) In Vivo and Pharmacokinetic Properties of the PharmaceuticalComposition

The pharmaceutical composition disclosed herein comprises at least oneimmediate release portion for immediate release of oxycodone andacetaminophen such that therapeutic plasma concentrations are quicklyattained (e.g., within one hour) and the initial onset of action isachieved within about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55minutes, or 60 minutes after administration of the composition upon oraladministration to a subject. The pharmaceutical composition disclosedherein also comprises at least one extended release portion forsustained release of oxycodone and acetaminophen over an extended periodof time, e.g., about 3 to about 12 hours, or about 4 to about 9 hours,or at least about 6 hours, or at least about 8 hours, to the uppergastrointestinal tract where acetaminophen, and potentially oxycodone,is best absorbed.

The pharmaceutical composition may be orally administered to a subjectonce in a 24 hour period (q.d. or once-daily), two times in a 24 hourperiod (b.i.d. or twice-daily), or three times in a 24 hour period(t.i.d. or three times daily). In one embodiment, the pharmaceuticalcomposition may be orally administered to the subject twice a day (i.e.,every 12 hours). The subject may be a mammal, and in certainembodiments, the subject may be a human.

In another embodiment, the subject may be administered a first orloading dose of the pharmaceutical composition. This first or loadingdose may assist the subject in more quickly attaining steady state bloodlevels of the active drugs. In a further embodiment, the subject may beadministered a first or loading dose of the pharmaceutical compositioncomprising about 22.5 mg of oxycodone and about 975 mg of acetaminophen.In yet another embodiment, the subject may be administered a first orloading dose of the pharmaceutical composition comprising 2 tablets,each tablet comprising about 11.25 mg of oxycodone and about 462.5 mg ofacetaminophen. In yet another embodiment, the subject may beadministered a first or loading dose of the pharmaceutical compositioncomprising 3 tablets, each tablet comprising about 7.5 mg of oxycodoneand about 325 mg of acetaminophen. In still another embodiment, thesubject may be administered a first or loading dose of thepharmaceutical composition comprising 4 tablets, each tablet comprisingabout 5.625 mg of oxycodone and about 231.25 mg of acetaminophen. In yetanother embodiment, the subject may be administered a first or loadingdose of the pharmaceutical composition comprising 2 capsules, eachcapsule comprising about 11.25 mg of oxycodone and about 462.5 mg ofacetaminophen. In yet another embodiment, the subject may beadministered a first or loading dose of the pharmaceutical compositioncomprising 3 capsules, each capsules comprising about 7.5 mg ofoxycodone and about 325 mg of acetaminophen. In still anotherembodiment, the subject may be administered a first or loading dose ofthe pharmaceutical composition comprising 4 capsules, each capsulescomprising about 5.625 mg of oxycodone and about 231.25 mg ofacetaminophen.

Upon oral administration to a subject, the pharmaceutical compositiondisclosed herein may maintain a therapeutic blood plasma concentrationof oxycodone of at least about 5 ng/mL from about 0.75 hours to about 12hours after administration of the composition. In another embodiment,the plasma concentration of oxycodone may be maintained at aconcentration of at least about 7.5 ng/mL from about 1 hour to about 12hours after administration of the composition. In a further embodiment,the plasma concentration of oxycodone may be maintained at aconcentration of at least about 7.5 ng/mL from about 0.75 hour to about10 hours after administration of the composition. In a furtherembodiment, the plasma concentration of oxycodone may be maintained at aconcentration of at least about 10 ng/mL from about 2 hour to about 10hours after administration of the composition. In yet anotherembodiment, the plasma concentration of oxycodone may be maintained at aconcentration of at least about 10 ng/mL from about 1 hour to about 10hours after administration of the composition. In still anotherembodiment, the plasma concentration of oxycodone may be maintained at aconcentration of at least about 10 ng/mL from about 0.75 hour to about10 hours after administration of the composition.

In another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya mean C_(max) (peak plasma concentration) for oxycodone from about 0.9ng/mL/mg to about 1.6 ng/mL/mg. In another embodiment, the mean C_(max)for oxycodone may range from about 1.0 ng/mL/mg to about 1.5 ng/mL/mg.In an additional embodiment, the mean C_(max) for oxycodone may be 0.9,1.0, 1.1, 1.2, 1.3, 1.4, 1.5, or 1.6 ng/mL/mg. Moreover, the meanC_(max) for oxycodone at steady state may range from about 1.5 ng/mL/mgto about 2.0 ng/mL/mg, from about 1.6 ng/mL/mg to about 1.95 ng/mL/mg,or from about 1.7 ng/mL/mg to about 1.85 ng/mL/mg.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, surprisingly may produce a blood plasmaconcentration profile characterized by a biphasic increase in bloodplasma concentrations of oxycodone. Deconvolution of the pharmaceuticalcomposition and the target plasma profiles can be done in WinNonLin(version 5.2, Pharsight Corp., Mountain View, Calif.). The results ofsuch a deconvolution analysis for oxycodone is depicted in FIG. 23. Thebiphasic absorption of oxycodone may be characterized by an initialrapid absorption resulting in a first peak in plasma concentrationbetween about 1 hour and 2 hours, which contributes to the early onsetof action, and a second peak in plasma concentrations between about 3hours and 7 hours as a result of slower absorption taking place from theat least one extended release portion after administration of thecomposition, which contributes to the duration or maintenance ofanalgesia. In some instances, the second peak may correspond to theoverall C_(max) of the composition. The biphasic increase in bloodplasma concentrations of oxycodone may be characterized by a plasmaconcentration-time profile for oxycodone in which the slope of a linedrawn between 0 hour and about 2 hours is greater than the slope of aline drawn between about 2 hours and about 5 hours. See FIG. 23.

This biphasic increase in oxycodone levels resulting from thecomposition has several benefits. For example, providing rapid but nottoo high concentrations of oxycodone for quick onset of analgesiafollowed by maintenance of oxycodone levels over an extended time periodcould prevent a human subject from developing liking or dependence(abuse) for oxycodone. Further fluctuations in the oxycodone plasmalevels could also prevent development of tolerance at the active site.Thus, the biphasic increase in oxycodone levels helps to prevent thisacute tolerance.

In an additional embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya mean AUC for oxycodone from about 9.0 ng·hr/mL/mg to about 18.5ng·hr/mL/mg. In a further embodiment, the mean AUC for oxycodone may befrom about 12.0 ng·hr/mL/mg to about 16.0 ng·hr/mL/mg. In anotherembodiment, the mean AUC for oxycodone may be about 9.0, 9.5, 10.0,10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, or16.0 ng·hr/mL/mg. Additionally, the mean AUC for oxycodone at steadystate may range from about 11.0 ng·hr/mL/mg to about 17.0 ng·hr/mL/mg,from about 12.0 ng·hr/mL/mg to about 16.0 ng·hr/mL/mg, or from about13.0 ng·hr/mL/mg to about 15.0 ng·hr/mL/mg.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya median T_(max) (time to peak plasma concentration) for oxycodone fromabout 2.0 hours to about 7.0 hours. In an alternate embodiment, themedian T_(max) for oxycodone may be from about 3.0 hours to about 6.0hours. In another embodiment, the median T_(max) for oxycodone may beabout 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or 6.0 hours. Moreover, themedian T_(max) for oxycodone at steady state may range from about 1.5hours to about 3.5 hours, or from about 2 hours to about 3 hours.

In still another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya median tlag for oxycodone from about 0 hours to about 0.5 hours. In analternate embodiment, the median tlag for oxycodone may be from about 0hours to about 0.25 hours.

Rates of absorption are often assessed by comparing standardpharmacokinetic parameters such as T_(max) and C_(max). The extent ofabsorption is assessed by the AUC. A short T_(max) has been used toindicate rapid absorption. The U.S. FDA, Guidance for Industry:Bioavailability and Bioequivalence Studies for Orally Administered DrugProducts—General Considerations (March 2003) and related publications(Chen et al, Clin. Pharmacokinet. 40 (8):565-72, 2001) also recommendsthe use of partial AUC for some modified-release drugs (“MR drugs”),such as the pharmaceutical compositions disclosed herein. A partial AUCcalculation may be used to measure early exposure to a drug, which maysignify an initial onset of pain relief and/or to measure prolongedexposure of a drug in achieving sustained relief. Partial AUCcalculations can also demonstrate whether two MR drugs are trulybioequivalent by comparing, for example, an early partial AUC, whichwill be associated with a drug's response onset, and a late partial AUC,which will be associated with a drug's sustained response. Theparameters for compositions vary greatly between subjects. Theparameters also vary depending on aspects of the study protocol such asthe sampling scheduling, subject posture and general subject health.Values quoted in this specification are given as mean±standard deviationunless otherwise noted.

For partial AUC calculations, the standard linear trapezoidal summationover each time interval is used. The partial AUCs are calculated fromthe mean pharmacokinetic profile. For time 0 to 1 hour the partial AUCis AUC_((0-1hr)); for time 0 to 2 hours the partial AUC isAUC_((0-2hr)); for time 0-4 hours the partial AUC is AUC_((0-4hr)); fortime 0 to 6 hour the partial AUC is AUC_((0-6hr)); for time 0 to 8 hoursthe partial AUC is AUC_((0-8hr)); and for time 0 to the last measurabletime point (“x”) the partial AUC is AUC_((0-(x)hr)) where each partialAUC is calculated according to standard pharmaceutical industrypharmacokinetic calculation methodologies as given by:

AUC_((0-1hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time zero to time 1 hour.

AUC_((0-2hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time zero to time 2 hours.

AUC_((0-4hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time zero to time 4 hours.

AUC_((0-6hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time zero to time 6 hours.

AUC_((0-8hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time zero to time 8 hours.

AUC_((0-(t)hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time zero to the last measurabletime point.

AUC_((0-(Tmax of IR product+2SD)))—Area under the drugconcentration-time curve calculated using linear trapezoidal summationfrom time zero to the time of the mean peak (T_(max)) for the immediaterelease version of the drug plus two standard deviations (“2SD”) for theimmediate release drug. The FDA has identified this calculation inassociation with an early onset of response for certain modified-releasedosage forms, which show complex pharmacokinetic characteristics. (Seesupra March 2003 Guidance; Draft Guidance on DexmethylphenidateHydrochloride (March 2012); Draft Guidance on MethylphenidateHydrocholoride (November 2011)).

AUC_(((Tmax of IR product+2SD)-t))—Area under the drugconcentration-time curve calculated using linear trapezoidal summationfrom the time of the mean peak (Tmax) for the immediate release versionof the drug plus two standard deviations (“2SD”) for the immediaterelease drug to the last measurable time point. The FDA has identifiedthis parameter in association with sustaining the response formodified-release dosage forms, which shows complex pharmacokineticcharacteristics. (See March 2003 Guidance supra; Draft Guidance onDexmethylphenidate Hydrochloride (March 2012); Draft Guidance onMethylphenidate Hydrocholoride (November 2011)).

AUC_((x-(y)hr))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time “x” (e.g., any measurabletime point, such as 8 hours) to time “y” (e.g., any other measurabletime point later than “x”, such as 12 hours).

AUC_((0-∞))—Area under the drug concentration-time curve calculatedusing linear trapezoidal summation from time 0 to infinity.

Further, partial AUC may be calculated using trapezoidal summation fromtime Tmax to time t (the last measured time point of plasmaconcentration profile).

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(0-1hr) for oxycodone from about 0.10 ng·hr/mL/mg to about 0.45ng·hr/mL/mg, from about 0.15 ng·hr/mL/mg to about 0.25 ng·hr/mL/mg, orfrom about 0.25 ng·hr/mL/mg to about 0.35 ng·hr/mL/mg. In anotherembodiment, the AUC_(0-1hr) for oxycodone may be about 0.10, 0.15, 0.20,0.25, 0.30, 0.35, 0.40, or 0.45 ng·hr/mL/mg.

In an additional embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(0-2hr) for oxycodone from about 0.65 ng·hr/mL/mg to about 1.35ng·hr/mL/mg, from about 0.80 ng·hr/mL/mg to about 1.0 ng·hr/mL/mg, orfrom about 1.0 ng·hr/mL/mg to about 1.2 ng·hr/mL/mg. In anotherembodiment, the AUC_(0-2hr) for oxycodone may be about 0.65, 0.70, 0.75,0.80, 0.85, 0.90, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30 or 1.35ng·hr/mL/mg.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(0-4hr) for oxycodone from about 2.0 ng·hr/mL/mg to about 4.0ng·hr/mL/mg, from about 2.5 ng·hr/mL/mg to about 3.0 ng·hr/mL/mg, orfrom about 3.0 ng·hr/mL/mg to about 3.5 ng·hr/mL/mg. In anotherembodiment, the AUC_(0-4hr) for oxycodone may be about 2.0, 2.5, 3.0,3.5, or 4.0 ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(Tmax-t) for oxycodone from about 5.0 ng·hr/mL/mg to about 16.0ng·hr/mL/mg, from about 8.0 ng·hr/mL/mg to about 10.5 ng·hr/mL/mg, orfrom about 10.5 ng·hr/mL/mg to about 14.0 ng·hr/mL/mg. In anotherembodiment, the AUC_(Tmax-t) for oxycodone may be about 5.0, 6.0, 7.0,8.0, 9.0, 10.0, 11.0, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0 or 16.0ng·hr/mL/mg.

In still another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-(Tmax of IR product+2SD))) for oxycodone after a single dosefrom about 1.0 ng·hr/mL/mg to about 3.0 ng·hr/mL/mg, from about 1.50ng·hr/mL/mg to about 2.5 ng·hr/mL/mg, or from about 1.75 ng·hr/mL/mg toabout 2.25 ng·hr/mL/mg. In another embodiment, theAUC_((0-(Tmax of IR product+2SD))) for oxycodone may be about 1.25, 1.3,1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95,2.0, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6,2.65, 2.7, or 2.75 ng·hr/mL/mg.

In one embodiment, the immediate release product referenced for thePartial AUC calculations is Percocet in the fasted state and thefollowing calculation was used to determineAUC_((0-(Tmax of IR product+2SD))):oxycodone mean±SD=1.0 h±0.89 h; Tmax+2SD=2.8 hoursIn such embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-2.8)) for oxycodone after a single dose from about 1.0ng·hr/mL/mg to about 3.0 ng·hr/mL/mg, from about 1.50 ng·hr/mL/mg toabout 2.5 ng·hr/mL/mg, or from about 1.75 ng·hr/mL/mg to about 2.25ng·hr/mL/mg. In another embodiment, the AUC_((0-2.8)) for oxycodone maybe about 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75,1.8, 1.85, 1.9, 1.95, 2.0, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4,2.45, 2.5, 2.55, 2.6, 2.65, 2.7, or 2.75 ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((2.8-48)) for oxycodone after a single dose from about 7.5ng·hr/mL/mg to about 15.0 ng·hr/mL/mg, from about 8.45 ng·hr/mL/mg toabout 13.7 ng·hr/mL/mg, or from about 9.5 ng·hr/mL/mg to about 11.5ng·hr/mL/mg. In another embodiment, the AUC_((2.8-48)) for oxycodone maybe about 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6,8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0,10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2,11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4,or 12.5 ng·hr/mL/mg.

In one embodiment, the immediate release product referenced for thePartial AUC calculations is Percocet in the fed state and the followingcalculation was used to determine AUC_((0-(Tmax of IR product+2SD))):oxycodone mean±SD=1.9 h±1.2 h; Tmax+2SD=4.3 hoursIn such embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-4.3)) for oxycodone after a single dose from about 1.5ng·hr/mL/mg to about 5.5 ng·hr/mL/mg, from about 2.0 ng·hr/ml/mg toabout 5.0 ng·hr/mL/mg, from about 2.5 ng·hr/mL/mg to about 4.5ng·hr/mL/mg, or from about 3.0 ng·hr/mL/mg to about 4.0 ng·hr/mL/mg. Inanother embodiment, the AUC_((0-4.3)) for oxycodone may be about 1.5,1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, 2.0, 2.05, 2.1, 2.15,2.2, 2.25, 2.3, 2.35, 2.4, 2.45, 2.5, 2.55, 2.6, 2.65, 2.7, 2.75, 2.8,2.85, 2.9, 2.95, 3.0, 3.05, 3.1, 3.15, 3.2, 3.25, 3.3, 3.35, 3.4, 3.45,3.5, 3.55, 3.6, 3.65, 3.7, 3.75, 3.8, 3.85, 3.9, 3.95, 4.0, 4.05, 4.1,4.15, 4.2, 4.25, 4.3, 4.35, 4.4, 4.45, 4.5, 4.55, 4.6, 4.65, 4.7, 4.75,4.8, 4.85, 4.9, 4.95, 5.0, 5.05, 5.1, 5.15, 5.2, 5.25, 5.3, 5.35, 5.4,5.45, or 5.5 ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((4.3-48)) for oxycodone after a single dose from about 5.0ng·hr/mL/mg to about 15.0 ng·hr/mL/mg, from about 7.5 ng·hr/mL/mg toabout 13.5 ng·hr/mL/mg, from about 9.0 ng·hr/mL/mg to about 12.0ng·hr/mL/mg, or from about 9.5 ng·hr/mL/mg to about 11.5 ng·hr/mL/mg. Inanother embodiment, the AUC_((4.3-48)) for oxycodone may be about 5.0,5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4,6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8,7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2,9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5,10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7,11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9,13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1,14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or 15.0 ng·hr/mL/mg.

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject in a fasted state, may produce a plasmaprofile characterized by an AUC_(8-12hr) for oxycodone from about 3% toabout 33% of the AUC_(0-t), from about 10% to about 27% of theAUC_(0-t), or from about 15% to about 22% of the AUC_(0-t). In anotherembodiment, the pharmaceutical composition, when orally administered toa subject in a fed state, may produce a plasma profile characterized byan AUC_(8-12hr) for oxycodone from about 5% to about 35% of theAUC_(0-t), from about 12% to about 30% of the AUC_(0-t), or from about15% to about 25% of the AUC_(0-t).

In an alternate embodiment, the pharmaceutical composition, when orallyadministered to a subject, may provide a mean half-life of oxycodonethat ranges from about 3.5 hours to about 5.5 hours, or from about 4hours to about 5 hours. In various embodiments, the mean half-life ofoxycodone may be about 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, or 5.2 hours.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, produces a plasma profile characterized by anabuse quotient for oxycodone from about 3 to about 5. In otherembodiments, the abuse quotient for oxycodone may be about 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, or 5.0.

Moreover, upon oral administration, the pharmaceutical compositiondisclosed herein may maintain a therapeutic plasma concentration ofacetaminophen of at least about 2 mg/mL from about 1 hour to about 6hours after administration. In another embodiment, the pharmaceuticalcomposition may maintain a therapeutic plasma concentration ofacetaminophen of at least about 2 mg/mL from about 0.75 hour to about6.5 hours after administration. In yet another embodiment, thecomposition may maintain a plasma concentration of acetaminophen of atleast about 1 mg/mL from about 0.5 hour to about 12 hours afteradministration.

In another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya mean C_(max) for acetaminophen from about 4.0 ng/mL/mg to about 11.0ng/mL/mg. In other embodiments, the mean C_(max) for acetaminophen maybe from about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0,9.5, 10.0, 10.5, or 11.0 ng/mL/mg. Moreover, the mean C_(max) foracetaminophen at steady state may range from about 6.0 ng/mL/mg to about9.0 ng/mL/mg, from about 6.5 ng/mL/mg to about 8.5 ng/mL/mg, or fromabout 7.0 ng/mL/mg to about 8.0 ng/mL/mg.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, surprisingly may produce a blood plasmaconcentration profile characterized by a biphasic increase in bloodplasma concentrations of acetaminophen. The biphasic absorption ofacetaminophen may characterized by an initial rapid absorption resultingin first peak in plasma concentrations between about 0.5 hour and 2hours, which contributes to the early onset on action, and a second peakin plasma concentrations between about 3 hours and 7 hours afteradministration of the composition, which contributes to the duration ormaintenance of analgesia. In some instances, the second peak maycorrespond to the overall C_(max) of the composition. The biphasicincrease in blood plasma concentrations of acetaminophen ischaracterized by a plasma concentration-time profile for acetaminophenin which the slope of a line drawn between 0 hour and 2 hour is greaterthan the slope of a line drawn between about 2 hours and 5 hours. SeeFIG. 24.

This biphasic increase in acetaminophen levels resulting from thecomposition has several benefits. For example, the initial rapid rise inplasma levels produce quick onset of analgesia and the slower absorptionprovides maintenance of analgesia for an extended period of time.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya mean AUC for acetaminophen from about 35.0 ng·hr/mL/mg to about 80.0ng·hr/mL/mg. In a further embodiment, the mean AUC for acetaminophen mayrange from about 35.0 ng·hr/mL/mg to about 60.0 ng·hr/mL/mg. In otherembodiments, the mean AUC for acetaminophen may be about 35.0, 40.0,45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, or 80.0 ng·hr/mL/mg.Additionally, the mean AUC for acetaminophen at steady state may rangefrom about 40.0 ng·hr/mL/mg to about 50.0 ng·hr/mL/mg, from about 35.0ng·hr/mL/mg to about 45.0 ng·hr/mL/mg, or from about 37.0 ng·hr/mL/mg toabout 42.0 ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition when orallyadministered to a subject, may produce a plasma profile characterized bya median T_(max) for acetaminophen from about 0.5 hours to about 6.0hours. In another embodiment, the median T_(max) for acetaminophen maybe from about 1.0 hour to about 5.0 hours. In a further embodiment, themedian T_(max) for acetaminophen may range from about 0.5 hour to about4.0 hours. In still another embodiment, the median T_(max) foracetaminophen may range from about 0.75 to about 1.5 hours. In otherembodiments, the median T_(max) may be about 0.5, 0.6, 0.7, 0.8, 0.9,1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 1.8, 1.9, 2.0, 2.2, 2.4, 2.6,2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, or 5.0 hours.Moreover, the median T_(max) for acetaminophen at steady state may rangefrom about 0.5 hour to about 1.0 hour, or from about 0.5 hour to about0.75 hour.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized bya median tlag for acetaminophen from about 0 hour to about 0.5 hour. Inan alternate embodiment, the median tlag for acetaminophen may be fromabout 0 hour to about 0.25 hour. In one embodiment, the median tlag foracetaminophen may be 0 hour. In another embodiment, the median tlag foracetaminophen may be 0.25 hour.

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byvarious partial AUCs for acetaminophen. The partial AUCs foracetaminophen are calculated as described above for oxycodone. Thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(0-1hr) foracetaminophen from about 1.25 ng·hr/mL/mg to about 3.25 ng·hr/mL/mg,from about 1.60 ng·hr/mL/mg to about 2.0 ng·hr/mL/mg, or from about 2.0ng·hr/mL/mg to about 2.75 ng·hr/mL/mg. In another embodiment, theAUC_(0-1hr) for acetaminophen may be about 1.25, 1.30, 1.40, 1.50, 1.55,1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, 2.0, 2.05, 2.10, 2.15,2.20, 2.25, 2.30, 2.35, 2.40, 2.45, 2.50, 2.55, 2.60, 2.65, 2.70, 2.75,2.80, 2.85, or 2.90 or ng·hr/mL/mg.

In an additional embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC₀₋₂ hr for acetaminophen from about 4.25 ng·hr/mL/mg to about 8.75ng·hr/mL/mg, from about 5.50 ng·hr/mL/mg to about 6.0 ng·hr/mL/mg, orfrom about 6.0 ng·hr/mL/mg to about 7.25 ng·hr/mL/mg. In anotherembodiment, the AUC_(0-2hr) for acetaminophen may be about 4.25, 4.5,4.75, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0, 7.25, 7.50, 7.75or 8.0 ng·hr/mL/mg.

In a further embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(0-4hr) for acetaminophen from about 10.0 ng·hr/mL/mg to about20.0 ng·hr/mL/mg, from about 13.0 ng·hr/mL/mg to about 14.5 ng·hr/mL/mg,or from about 14.5 ng·hr/mL/mg to about 16.5 ng·hr/mL/mg. In anotherembodiment, the AUC_(0-4hr) for acetaminophen may be about 10.0, 11.0,12.0, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, or 17.0ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(Tmax-t) for acetaminophen from about 20.0 ng·hr/mL/mg to about40.0 ng·hr/mL/mg, from about 23.5 ng·hr/mL/mg to about 36.0 ng·hr/mL/mg,or from about 29.0 ng·hr/mL/mg to about 31.0 ng·hr/mL/mg. In anotherembodiment, the AUC_(Tmax-t) for acetaminophen may be about 20.0, 21.0,22.0, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0,28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0,34.5, 35.0, 35.5 or 36.0 ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-(Tmax of IR product+2SD))) for acetaminophen after a singledose from about 5.0 ng·hr/mL/mg to about 13.0 ng·hr/mL/mg, from about7.2 ng·hr/mL/mg to about 11.6 ng·hr/mL/mg, or from about 8.5 ng·hr/mL/mgto about 10.0 ng·hr/mL/mg. In another embodiment, theAUC_((0-(Tmax of IR product+2SD))) for acetaminophen may be about 5.0,6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3,7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7,8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1,10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3,11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12.0 ng·hr/mL/mg.

In one embodiment, the immediate release product referenced for thePartial AUC calculations is Percocet in the fasted state and thefollowing calculation was used to determineAUC_((0-(Tmax of IR product+2SD))):acetaminophen mean±SD=0.596 h±0.529 h; Tmax+2SD=1.65 hourIn such embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-1.7)) for acetaminophen after a single dose from about 5.0ng·hr/mL/mg to about 13.0 ng·hr/mL/mg, from about 7.2 ng·hr/mL/mg toabout 11.6 ng·hr/mL/mg, or from about 8.5 ng·hr/mL/mg to about 10.0ng·hr/mL/mg. In another embodiment, the AUC_((0-1.7)) for acetaminophenmay be about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9,9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2,10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4,11.5, 11.6, 11.7, 11.8, 11.9, or 12.0 ng·hr/mL/mg.

In still a further embodiment, the pharmaceutical composition, whenorally administered to a subject, may produce a plasma profilecharacterized by an AUC_((1.7-48)) for acetaminophen after a single dosefrom about 25.0 ng·hr/mL/mg to about 75.0 ng·hr/mL/mg, from about 31.5ng·hr/mL/mg to about 55.0 ng·hr/mL/mg, or from about 35.0 ng·hr/mL/mg toabout 50.0 ng·hr/mL/mg. In another embodiment, the AUC_((1.7-48)) foracetaminophen may be about 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0,28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0,34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0,40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0,46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0,52.5, 53.0, 53.5, 54.0, 54.5, or 55.0 ng·hr/mL/mg.

In one embodiment, the immediate release product referenced for thePartial AUC calculations is Percocet in the fed state and the followingcalculation was used to determine AUC_((0-(Tmax of IR product+2SD))):acetaminophen mean±SD=1.48 h±0.875 h; Tmax+2SD=3.2 hourIn such embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-3.2)) for acetaminophen after a single dose from about 7.0ng·hr/mL/mg to about 21.0 ng·hr/mL/mg, from about 9.0 ng·hr/mL/mg toabout 18.0 ng·hr/mL/mg, from about 10.0 ng·hr/mL/mg to about 16.0ng·hr/mL/mg, or from about 12.0 ng·hr/mL/mg to about 15.0 ng·hr/mL/mg.In another embodiment, the AUC_((0-3.2)) for acetaminophen may be about7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3,8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9,11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1,12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3,13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5,14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7,15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9,17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1,18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3,19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5,20.6, 20.7, 20.8, 20.9, or 21.0 ng·hr/mL/mg.

In still a further embodiment, the pharmaceutical composition, whenorally administered to a subject, may produce a plasma profilecharacterized by an AUC_((3.2-48)) for acetaminophen after a single dosefrom about 15.0 ng·hr/mL/mg to about 75.0 ng·hr/mL/mg, from about 25.0ng·hr/mL/mg to about 55.0 ng·hr/mL/mg, from about 27.5 ng·hr/mL/mg toabout 45.0 ng·hr/mL/mg, or from about 30.0 ng·hr/mL/mg to about 40.0ng·hr/ml/mg. In another embodiment, the AUC_((3.2-48)) for acetaminophenmay be about 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5,20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5,26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5,32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5,38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5,44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5,50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0, 53.5, 54.0, 54.5, 55.0, 55.5,56.0, 56.5, 57.0, 57.5, 58.0, 58.5, 59.0, 59.5, 60.0, 60.5, 61.0, 61.5,62.0, 62.5, 63.0, 63.5, 64.0, 64.5, 65.0, 65.5, 66.0, 66.5, 67.0, 67.5,68.0, 68.5, 69.0, 69.5, 70.0, 70.5, 71.0, 71.5, 72.0, 72.5, 73.0, 73.5,74.0, 74.5, or 75.0 ng·hr/mL/mg.

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(0-12hr) for acetaminophen from about 20.0 ng·hr/mL/mg to about60.0 ng·hr/mL/mg, from about 30 ng·hr/mL/mg to about 50 ng·hr/mL/mg,from about 35 to about 45 ng·hr/mL/mg, or from about 37.5 ng·hr/mL/mg toabout 42.5 ng·hr/mL/mg. In another embodiment, the pharmaceuticalcomposition, when orally administered to a subject, may produce a plasmaprofile characterized by an AUC_(0-12hr) for acetaminophen from about20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5,26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5,32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5,38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5,44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5,50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0, 53.5, 54.0, 54.5, or 55.0. Ina further embodiment, at AUC_(0-12hr) between about 70%-95%, about75%-92%, or about 77%-90% of the acetaminophen has been cleared. Instill another embodiment, about 80% of the acetaminophen has beencleared.

In another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(1-12hr) for acetaminophen from about 15.0 ng·hr/mL/mg to about55.0 ng·hr/mL/mg, from about 25.0 ng·hr/mL/mg to about 45.0 ng·hr/mL/mg,or from about 30.0 to about 40.0 ng·hr/mL/mg. In another embodiment, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(1-12hr) foracetaminophen from about 15, 16, 17, 18, 19, 20.0, 20.5, 21.0, 21.5,22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5,28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5,34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5,40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5,46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, or 50.0 ng·hr/mL/mg.

In yet another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(12-36hr) for acetaminophen from about 5.0 ng·hr/mL/mg to about25.0 ng·hr/mL/mg, from about 7.5 ng·hr/mL/mg to about 20.0 ng·hr/mL/mg,or from about 10.0 ng·hr/mL/mg to about 15.0. In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(12-36hr) foracetaminophen from about 5.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1,8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7,10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9,12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1,13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3,14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or 15.0 ng·hr/mL/mg.

In another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(8-12hr) for acetaminophen from about 1.5 ng·hr/mL/mg to about15.5 ng·hr/mL/mg, from about 2 ng·hr/mL/mg to about 12.25 ng·hr/mL/mg,from about 3.5 ng·hr/mL/mg to about 10 ng·hr/mL/mg, or from about 4.5ng·hr/mL/mg to about 6.5 ng·hr/mL/mg. In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(8-12hr) foracetaminophen from about 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.1, 3.2,3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6,4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8,8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2,10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4,11.5, 11.6, 11.7, 11.8, 11.9, or 12.0 ng·hr/mL/mg.

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((0-3hr)) for acetaminophen from about 5 ng·hr/mL/mg to about 30ng·hr/mL/mg, from about 10 ng·hr/mL/mg to about 20 ng·hr/mL/mg, or fromabout 13 ng·hr/mL/mg to about 17 ng·hr/mL/mg. In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_((0-3hr)) foracetaminophen from about 5.0, 6.0, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3,10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5,11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9,14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1,15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3,16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5,17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7,18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9,or 20.0 ng·hr/mL/mg.

In another embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_((3-36hr)) for acetaminophen from about 20 ng·hr/mL/mg to about50 ng·hr/mL/mg, from about 20 ng·hr/mL/mg to about 40 ng·hr/mL/mg, orfrom about 25 ng·hr/mL/mg to about 35 ng·hr/mL/mg. In other embodiments,the pharmaceutical composition, when orally administered to a subject,may produce a plasma profile characterized by an AUC_((3-36hr)) foracetaminophen from about 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24,24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31,31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38,38.5, 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43, 43.5, 44, 44.5, 45,45.5, 46, 46.5, 47, 47.5, 48, 48.5, 49, 49.5, or 50 ng·hr/mL/mg.

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(0-12hr) for acetaminophen from about 50% to about 90% of theAUC_(0-t), from about 55% to about 85% of the AUC_(0-t), or from about75% to about 85% of the AUC_(0-t). In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(0-12hr) foracetaminophen that is about 50%, 55%, 60%, 65%, 70%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84% or 85% of the AUC_(0-t).

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(1-12hr) for acetaminophen from about 40% to about 90% of theAUC_(0-t), from about 55% to about 85% of the AUC_(0-t), or from about60% to about 75% of the AUC_(0-t). In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(1-12hr) foracetaminophen of about 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%,66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or80% of the AUC_(0-t).

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(12-36hr) for acetaminophen from about 10% to about 40% of theAUC_(0-t), from about 15% to about 35% of the AUC_(0-t), or from about20% to about 30% of the AUC_(0-t). In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(12-36hr) foracetaminophen of about 10%, 12%, 14%, 16%, 18%, 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, or 30% of the AUC_(0-t).

In one embodiment, the pharmaceutical composition, when orallyadministered to a subject, may produce a plasma profile characterized byan AUC_(8-12hr) for acetaminophen from about 5% to about 30% of theAUC_(0-t), from about 7% to about 25% of the AUC_(0-t), or from about10% to about 20% of the AUC_(0-t). In other embodiments, thepharmaceutical composition, when orally administered to a subject, mayproduce a plasma profile characterized by an AUC_(8-12hr) foracetaminophen of about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the AUC_(0-t).

In an alternate embodiment, the pharmaceutical composition, when orallyadministered to a subject, may have a mean half-life of acetaminophenthat ranges from about 2 hours to about 10 hours, or from about 3 hoursto about 6 hours. In another embodiment, the pharmaceutical composition,when orally administered to a subject, may have a mean half-life ofacetaminophen that ranges from about 3 hours to about 5 hours. In stillanother embodiment, the pharmaceutical composition, when orallyadministered to a subject, may have a mean half-life of acetaminophenthat ranges from about 4 hours to about 5 hours. In various embodiments,the mean half-life of acetaminophen may be about 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 5.5, 6.0, 6.5, 6.0, 7.0, 7.5, or 8 hours. In additionalembodiments, the pharmaceutical composition, when orally administered toa subject, has a mean observed half-life of acetaminophen that is morethan the mean half-life of commercially available immediate releaseacetaminophen products.

In another embodiment, upon administration of the pharmaceuticalcomposition to a subject, the composition may provide at least about 4hours to about 12 hours of drug delivery to the upper gastrointestinaltract, which includes the duodenum, jejunum, and ileum of the smallintestine. In another embodiment, the composition may provide at leastabout 6 hours of drug delivery to the upper gastrointestinal tract. Inyet a further embodiment, the composition may provide at least about 8hours of drug delivery to the upper gastrointestinal tract. In yet afurther embodiment, the composition may provide at least about 9 hours,or at least about 10 hours of drug delivery to the uppergastrointestinal tract.

In yet another embodiment, upon administration of the pharmaceuticalcomposition to a subject, APAP undergoes presystemic metabolism in thegut and/or liver allowing only a fraction of the drug to reach thesystemic circulation. The fraction of drug that is originally absorbedprior to pre-systemic metabolism is referred to as the fraction absorbedand denoted “Fab.” This is different from the fraction bioavailable “F,”which is the fraction that reaches the systemic circulation after themetabolism in the gut and liver.

In another embodiment, 60-90% of the acetaminophen in the pharmaceuticalcomposition, which is available for absorption into the systemiccirculation, is absorbed in the upper gastrointestinal tract. In stillanother embodiment, 60-85% of acetaminophen in the pharmaceuticalcomposition, which is available for absorption into the systemiccirculation, is absorbed in the duodenum and jejunum. See FIG. 27.Greater than 50% absorption of acetaminophen in the uppergastrointestinal tract is beneficial to a human subject becauseacetaminophen is poorly absorbed in the stomach and well absorbed in thesmall intestine and particularly, the upper segment of thegastrointestinal tract. It is therefore critical that acetaminophen isavailable in upper small intestine for its absorption. In one embodimentacetaminophen is released in stomach and reaches quickly into upper partof the small intestine for the absorption to take place.

In another embodiment, when about 60% to about 75% of the acetaminophenis released from the dosage form in the stomach within 2 hours followingoral administration, about 10% to about 25% of the total amount of theacetaminophen in the dosage form, which is available for absorption intothe systemic circulation, is absorbed in the duodenum, about 25% toabout 40% is absorbed in the proximal jejunum (noted as “jejunum 1” inFIG. 27), about 15% to about 20% is absorbed in the distal jejunum(noted as “jejunum 2” in FIG. 27), and about 5% to about 15% is absorbedin the ileum.

In another embodiment, when about 70% to about 90% of the acetaminophenis released from the dosage form in the stomach within 4 hours followingoral administration, about 10% to about 25% of the total amount of theacetaminophen in the dosage form, which is available for absorption intothe systemic circulation, is absorbed in the duodenum, about 25% toabout 40% is absorbed in the proximal jejunum (noted as “jejunum 1” inFIG. 27), about 15% to about 20% is absorbed in the distal jejunum(noted as “jejunum 2” in FIG. 27), and about 5% to about 15% is absorbedin the ileum.

In yet another embodiment, when at least about 55% of the total amountof the acetaminophen is released from the dosage form in the stomachwithin 1 hour after oral administration and when at least about 60% ofthe acetaminophen is released in the stomach after 2 hours, about 15% toabout 20% of the total amount of the acetaminophen in the dosage form,which is available for absorption into the systemic circulation, isabsorbed in the duodenum, about 30% to about 37% is absorbed in theproximal jejunum, about 15% to about 18% is absorbed in the distaljejunum, and about 8% to about 10% is absorbed in the ileum.

In still another embodiment, upon administration of the pharmaceuticalcomposition to a subject, the opioid undergoes presystemic metabolism inthe gut and/or liver allowing only a fraction of the drug to reach thesystemic circulation. The fraction of drug that is originally absorbedprior to pre-systemic metabolism is referred to as the fraction absorbedand denoted “Fab.” In one embodiment, the opioid is oxycodone. This isdifferent from the fraction bioavailable “F,” which is the fraction thatreaches the systemic circulation after metabolism in the gut and liver.

In a further embodiment, 70-95% of the oxycodone in the pharmaceuticalcomposition, which is available for absorption into the systemiccirculation, is absorbed in the upper gastrointestinal tract. In stillanother embodiment, 80-95% of oxycodone in the pharmaceuticalcomposition, which is available for absorption into the systemiccirculation, is absorbed in the duodenum and jejunum. See FIG. 28.

In one embodiment, the composition releases the opioid and other API inthe stomach to optimize drug absorption in the duodenum and jejunum. Forexample, when about 25% to about 50% of oxycodone is released from thedosage form in the stomach within 1 hour following oral administration,about 10% to about 45% of the total amount of the oxycodone in thedosage form, which is available for absorption into the systemiccirculation, is absorbed in the duodenum, about 25% to about 50% isabsorbed in the proximal jejunum (noted as “jejunum 1” in FIG. 28),about 7% to about 20% is absorbed in the distal jejunum (noted as“jejunum 2” in FIG. 28), and about 2% to about 15% is absorbed in theileum.

In another embodiment, when about 45% to about 65% of oxycodone isreleased from the dosage form in the stomach within 2 hours followingoral administration, about 10% to about 50% of the total amount of theoxycodone in the dosage form, which is available for absorption into thesystemic circulation, is absorbed in the duodenum, about 25% to about55% is absorbed in the proximal jejunum (noted as “jejunum 1” in FIG.28), about 5% to about 25% is absorbed in the distal jejunum (noted as“jejunum 2” in FIG. 28), and about 2% to about 15% is absorbed in theileum.

In another embodiment, when about 60% to about 85% of oxycodone isreleased from the dosage form in the stomach within 4 hours followingoral administration, about 10% to about 55% of the total amount of theoxycodone in the dosage form, which is available for absorption into thesystemic circulation, is absorbed in the duodenum, about 30% to about60% is absorbed in the proximal jejunum (noted as “jejunum 1” in FIG.28), about 10% to about 30% is absorbed in the distal jejunum (noted as“jejunum 2” in FIG. 28), and about 2% to about 20% is absorbed in theileum.

In yet another embodiment, when at least 25% of the total amount of theoxycodone is released from the dosage form in the stomach within 1 hourafter oral administration and when at least 45% of the oxycodone isreleased in the stomach after 2 hours, about 30% to about 45% of thetotal amount of oxycodone in the dosage form, which is available forabsorption into the systemic circulation, is absorbed in the duodenum,about 37% to about 43% is absorbed in the proximal jejunum (noted as“jejunum 1” in FIG. 28), about 10% to about 15% is absorbed in thedistal jejunum (noted as “jejunum 2” in FIG. 28), and about 2% to about8% is absorbed in the ileum.

In another embodiment, about 90% to about 100% of the IR dose ofacetaminophen is released within about 15 minutes, 30 minutes, 45minutes or 60 minutes after oral administration. In one embodiment, thedosage form provides a dissolution profile wherein about 20% to about65%, about 35% to about 55% or about 40% to about 50% of the ER dose ofacetaminophen remains in the ER layer between about 1 and 2 hours afteradministration. In one embodiment, not more than 50% of the ER dose ofacetaminophen is released within about the first hour. In a furtherembodiment, not more than 45% or not more than 40% of the ER dose ofacetaminophen is released within about the first hour. In anotherembodiment, not more than 85% of the ER dose of acetaminophen isreleased within about 4 hours. In yet another embodiment, not less than50% is released after about 6 hours. In yet another embodiment, not lessthan 60% is released after about 6 hours. In one embodiment, the ER doseof acetaminophen is released over a time period of about 6 to 12, about8 to 10, or about 9 to 10 hours in vitro. In another embodiment, the ERdose of acetaminophen is released over a time period of about 7 hours, 8hours, 9 hours, 10 hours, 11 hours or 12 hours in vitro. In anotherembodiment, at least 90% or 95% of the ER dose of acetaminophen isreleased over a time period of about 7 hours, 8 hours, 9 hours, 10hours, 11 hours or 12 hours in vitro.

In one embodiment, the pharmaceutical compositions disclosed hereinrapidly achieve therapeutic plasma drug levels of oxycodone andacetaminophen similar to an immediate release product, which provides anearly onset of action within about the first 5 minutes, 10 minutes, 15minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45minutes, 50 minutes, 55 minutes or 60 minutes after administration ofthe composition, but unlike an immediate release product, thepharmaceutical composition is able to maintain those therapeutic plasmadrug levels of oxycodone and acetaminophen over an extended period oftime (e.g., up to 12 hours). Currently, there is no pharmaceuticalcomposition available comprising oxycodone and acetaminophen which isable to provide a patient with quick onset of analgesia and maintenanceof analgesia for an extended period of time.

In yet another embodiment, upon average, within one hour ofadministration to a subject, the pharmaceutical composition achieves aCmax for acetaminophen. The Cmax achieved by the pharmaceuticalcomposition disclosed herein is comparable to the Cmax obtained from acommercially-available immediate release product containingacetaminophen formulated at half the strength of thecommercially-available immediate release product. The acetaminophencontinues to be released from the pharmaceutical composition at a rateless than the clearance rate for the acetaminophen, so that theacetaminophen levels fall smoothly until all of the acetaminophen isabsorbed. Stated another way, the acetaminophen released by thepharmaceutical composition is eliminated by the body faster than it isbeing absorbed. The absorption of the acetaminophen released from thepharmaceutical composition is complete in about 8 to about 10 hours sothat for one half life of acetaminophen the blood supply reaching thesubject's liver via the portal vein contains no additional amounts ofacetaminophen beyond the amounts present in the subject's generalcirculation.

These additional amounts of acetaminophen delivered to the liver fromthe subject's portal vein are frequently caused by the absorption ofacetaminophen in the subject's gastrointestinal tract. Indeed, bloodfrom the subject's intestines passes through the liver and then on tothe general circulation. When acetaminophen is undergoing absorption,blood containing acetaminophen from the absorption process passesthrough the subject's liver prior to entering the general circulationwhere the acetaminophen is diluted by the distribution and clearanceprocesses. The metabolism of these higher acetaminophen concentrationsin blood coming into the subject's liver is termed the “first passeffect.” Hence, the absorption process for acetaminophen taxes asubject's metabolic systems in the liver due to these higher “firstpass” concentrations. Once the absorption process is complete, theconcentration of acetaminophen in the blood reaching the subject's liverthrough the portal vein will be the same concentration of acetaminophenas found in blood throughout the rest of the subject's body. Thus, thepharmaceutical compositions disclosed herein provide a Cmax comparableto a commercially-available immediate-release acetaminophen product(dosed at half strength) while providing a less taxing burden on thesubject's metabolic systems in the liver because the acetaminophenreleased by the pharmaceutical composition is eliminated by thesubject's body faster than it is being absorbed. This results indecreased levels of acetaminophen in a subject's liver as compared to animmediate release dosage form of acetaminophen dosed every 6 hours.

(h) Exemplary Compositions

In one embodiment, the pharmaceutical composition for extended releaseof oxycodone and acetaminophen comprises at least one extended releaseportion comprising acetaminophen, oxycodone or a combination thereof,and at least one extended release component; and at least one immediaterelease portion comprising oxycodone, acetaminophen or combinationsthereof. In yet another embodiment, the pharmaceutical compositioncomprises an immediate release portion comprising oxycodone andacetaminophen and an extended release portion comprising oxycodone,acetaminophen and an extended release component. In still yet anotherembodiment, the composition comprises two extended release portions,each comprising an extended release component and one of the oxycodoneor the acetaminophen, and an immediate release portion comprising theoxycodone and the acetaminophen. In another embodiment, the compositioncomprises two extended release portions, each comprising an extendedrelease component and one of oxycodone or acetaminophen, and twoimmediate release portions, each comprising one of oxycodone oracetaminophen. In one embodiment, the extended release componentcomprises at least one extended release polymer. In another oneembodiment, the extended release polymer comprises a polyethylene oxide.The molecular weight of the polyethylene oxide may be from about 500,000Daltons to about 10,000,000 Daltons.

In another embodiment, the pharmaceutical composition may comprise fromabout 5 mg to about 30 mg of oxycodone and from about 250 mg to about1300 mg of acetaminophen. In one exemplary embodiment, thepharmaceutical composition may comprise about 15 mg of oxycodone andabout 650 mg of acetaminophen. In another exemplary embodiment, thecomposition may comprise about 15 mg of oxycodone and about 500 mg ofacetaminophen. In yet another exemplary embodiment, the composition maycomprise about 15 mg of oxycodone and about 325 mg of acetaminophen. Ina further embodiment, the composition may comprise about 30 mg ofoxycodone and about 500 mg of acetaminophen. In yet another exemplaryembodiment, the pharmaceutical composition may comprise about 7.5 mg ofoxycodone about 325 mg of acetaminophen. In still another exemplaryembodiment, the pharmaceutical composition may comprise about 10 mg ofoxycodone about 325 mg of acetaminophen. In a further exemplaryembodiment, the pharmaceutical composition may comprise about 20 mg ofoxycodone about 650 mg of acetaminophen. In another exemplaryembodiment, the composition may comprise about 30 mg of oxycodone andabout 650 mg of acetaminophen. In yet another exemplary embodiment, thecomposition may comprise about 22.5 mg of oxycodone and about 925 mg ofacetaminophen.

In a further embodiment, a single dosage form of the pharmaceuticalcomposition disclosed herein (e.g., one tablet) will provide a subjectwith approximately the same therapeutic benefit and pharmacokineticprofile as either two dosage forms (e.g., two tablets) of thecomposition formulated at half the strength, or three dosage forms(e.g., three tablets) of the composition formulated at a third of thestrength. In yet another exemplary embodiment, the pharmaceuticalcomposition comprising 15 mg of oxycodone and 650 mg of acetaminophen ina single dosage form (e.g., one tablet) will provide a subject withapproximately the same therapeutic benefit and pharmacokinetic profileas two dosage forms of the pharmaceutical composition formulated at halfthe strength (e.g., each tablet comprising 7.5 mg of oxycodone and 325mg of acetaminophen). In still another exemplary embodiment, thepharmaceutical composition comprising 15 mg of oxycodone and 650 mg ofacetaminophen in a single dosage form (e.g., one tablet) will provide asubject with approximately the same therapeutic benefit andpharmacokinetic profile as three dosage forms of the pharmaceuticalcomposition formulated at a third of the strength (e.g., each tabletcomprising 5 mg of oxycodone and about 216.7 mg of acetaminophen). Inyet another embodiment, the pharmaceutical composition comprising 15 mgof oxycodone and 325 mg of acetaminophen in a single dosage form (e.g.,one tablet) taken together with another tablet comprising 7.5 mg ofoxycodone and 325 mg of acetaminophen in a single dosage form willprovide a subject with approximately the same therapeutic benefit andpharmacokinetic profile as a single tablet comprising 22.5 mg ofoxycodone and 650 mg of acetaminophen. In still another exemplaryembodiment, the pharmaceutical composition comprising 15 mg of oxycodoneand 325 mg of acetaminophen in a single dosage form (e.g., one tablet)taken together with another tablet comprising 15 mg of oxycodone and 325mg of acetaminophen in a single dosage form will provide a subject withapproximately the same therapeutic benefit and pharmacokinetic profileas a single tablet configuration totaling 30 mg of oxycodone and 650 mgof acetaminophen. In yet a further exemplary embodiment, apharmaceutical composition comprising 21 mg of oxycodone and 650 mg ofacetaminophen in a single dosage form (e.g., one tablet) will provide asubject with approximately the same therapeutic benefit andpharmacokinetic profile as two dosage forms of the pharmaceuticalcomposition formulated at half the strength (e.g., each tabletcomprising 10.5 mg of oxycodone and 325 mg of acetaminophen). In yetanother exemplary embodiment, a pharmaceutical composition comprising22.5 mg of oxycodone and 925 mg of acetaminophen in a single dosage form(e.g., one tablet) will provide a subject with approximately the sametherapeutic benefit and pharmacokinetic profile as three dosage forms ofthe pharmaceutical composition formulated at a third of the strength(e.g., each tablet comprising 7.5 mg of oxycodone and 325 mg ofacetaminophen).

In yet another embodiment, the at least one extended release portion ofthe composition may comprise from about 40% to about 60% (w/w) of thetotal amount of acetaminophen in the composition and from about 70% toabout 80% (w/w) of the total amount of oxycodone in the composition,whereas the at least one immediate release portion may comprise fromabout 40% to about 60% (w/w) of the total amount of acetaminophen in thecomposition and from about 20% to about 30% (w/w) of the total amount ofoxycodone in the composition. In still another embodiment, the at leastone extended release portion may comprise about 50% (w/w) of the totalamount of acetaminophen in the composition and about 75% (w/w) of thetotal amount of oxycodone in the composition; and the at least oneimmediate release portion may comprise about 50% (w/w) of total amountof acetaminophen in the composition and about 25% (w/w) of the totalamount of oxycodone in the composition.

In another embodiment, an extended release portion of the compositionmay comprise, by weight of such extended release portion, from about 30%to about 50% of the extended release polymer, from about 20% to about40% of acetaminophen, and from about 0.5% to about 2% of oxycodone; andan immediate release portion may comprise, by weight of such immediaterelease portion, from about 70% to about 80% acetaminophen and fromabout 0.5% to about 1% of oxycodone.

In yet another embodiment, the pharmaceutical composition may comprisefrom about 7.5 mg to about 30 mg of oxycodone and from about 325 mg toabout 650 mg of acetaminophen, wherein the at least one immediaterelease portion may comprise about 25% (w/w) of the total amount ofoxycodone in the composition and about 50% (w/w) of the total amount ofacetaminophen in the composition, and the at least one extended releaseportion may comprise about 75% (w/w) of the total amount of oxycodone inthe composition, about 50% (w/w) of the total amount of acetaminophen inthe composition, and about 35% to about 45%, by weight of the at leastone extended release portion, of an extended release polymer comprisinga polyethylene oxide.

Other exemplary formulations are set forth in Charts 1-2 below:

CHART 1 Representative Oxycodone/Acetaminophen Formulations. FormulationNo. 1 2 3 4 5 6 7 8 9 10 Immediate APAP 185.3 175.0 180.0 160.4 200.0193.4 118.8 162.5 139.0 150.0 Release Oxycodone 1.100 1.75 2.00 2.501.25 1.00 2.75 1.875 1.75 1.875 Layer hydrochloride Microcrystalline23.0 17.0 19.0 27.0 16.0 18.0 18.0 14.0 21.0 24.0 cellulosePregelatinized 0.05 0.15 0.25 0.10 0.05 0.30 0.20 0.25 0.15 0.20 starchCitric Acid 0.08 0.08 0.08 0.11 0.11 0.14 0.07 0.13 0.15 0.17 AnhydrousEDTA disodium 0.087 0.106 0.075 0.03 0.050 0.055 0.033 0.025 0.045 0.018salt, dihydrate Hydroxypropyl 14.1 17.8 — — 17.3 — 16.7 16.1 21.5 —cellulose Hypromellose 2.5 — 3.2 — — — — — 8.9 19.5 Hydroxypropyl — —21.7 18.3 — 19.3 — — — 3.0 methyl cellulose Croscarmellose 10.0 11.011.5 11.5 13.0 14.5 14.5 12.5 14.0 12.5 sodium Silicon dioxide 0.97 0.751.14 1.02 1.10 1.03 0.88 1.05 0.93 2.30 Magnesium 1.5 1.0 1.0 0.5 0.52.0 2.0 0.5 1.5 2.5 stearate Extended APAP 185.3 150.0 145.0 155.2 125.0100.5 146.9 162.5 207.4 150.0 Release Oxycodone 6.900 5.75 5.50 5.006.25 6.50 7.25 5.625 4.75 6.625 Layer hydrochloride Microcrystalline175.4 180.0 302.2 275.0 214.8 250.0 245.7 203.6 288.3 200.5 cellulosePregelatinized 0.60 0.60 0.70 0.70 0.70 0.75 0.75 0.75 0.85 0.85 starchCitric Acid 0.24 0.16 0.24 0.22 0.33 0.28 0.07 0.38 0.45 0.34 AnhydrousEDTA disodium 0.160 0.085 0.095 0.055 0.130 0.065 0.065 0.075 0.1300.125 salt, dihydrate Hydroxypropyl 30.0 275.8 95.5 210.6 13.2 40.7 32.99.6 — — cellulose Polyox N12K 292.8 — — — 287.7 — — — 155.5 — Polyox1105 — — 244.2 — — — 275.5 321.8 — 189.2 Hydroxypropyl — 103.2 — 134.2 —182.2 — — 155.5 210.2 methyl cellulose Silicon Dioxide 1.8 1.3 1.5 2.32.4 3.0 3.5 3.6 2.0 2.5 Magnesium 7.5 8.0 7.4 8.1 7.5 10.2 9.9 7.2 10.310.3 Stearate Formulation No. 11 12 13 14 15 16 17 18 19 20 ImmediateAPAP 300.0 150.0 200.0 150.0 100.0 160.0 190.0 75.0 90.0 125.0 ReleaseOxycodone 2.00 1.00 1.50 3.50 2.75 1.25 1.25 2.50 1.75 3.00 Layerhydrochloride Microcrystalline 21.5 18.5 25.3 35.0 15.7 27.1 9.9 13.924.2 16.9 cellulose Pregelatinized 0.03 0.30 0.25 0.27 0.08 0.35 0.750.09 0.15 0.26 starch Citric Acid 0.12 0.08 0.09 0.16 0.07 0.24 0.140.26 0.15 0.20 Anhydrous EDTA disodium 0.04 0.175 0.1 0.06 0.1 0.09 0.060.08 0.063 0.09 salt, dihydrate Hydroxypropyl — 21.5 1.8 9.8 14.8 — 20.819.2 25.4 — cellulose Hypromellose 2.5 — — — — — — — 10.3 22.5Hydroxypropyl 16.3 11.4 17.5 8.7 — 29.3 — — — 4.4 methyl celluloseCroscarmellose 6.8 11.0 12.8 7.9 19.0 9.6 13.3 15.6 15.1 14.7 sodiumSilicon dioxide 0.86 0.80 2.25 1.24 .95 1.34 0.80 1.66 0.79 2.37Magnesium 1.75 1.0 0.75 0.6 0.5 2.5 1.9 0.8 1.2 2.8 stearate ExtendedAPAP 150.0 150.0 125.0 75.0 100.0 165.0 135.0 225.0 210.0 150.0 ReleaseOxycodone 8.00 6.50 6.00 6.50 3.25 6.25 6.25 5.00 6.25 5.50 Layerhydrochloride Microcrystalline 182.2 197.6 300.4 269.6 210.0 275.5 283.2310.2 240.8 210.0 cellulose Pregelatinized 0.75 0.73 0.46 0.89 0.55 0.780.55 0.65 0.67 0.64 starch Citric Acid 0.25 0.36 0.38 0.34 0.37 0.230.14 0.40 0.70 0.70 Anhydrous EDTA disodium 0.23 0.09 0.14 0.06 0.1830.035 0.049 0.03 0.105 0.075 salt, dihydrate Hydroxypropyl 34.7 321.988.4 212.9 11.9 37.7 34.2 17.4 — — cellulose Polyox N12K — — 252.4 —290.3 — 248.2 279.2 175.2 — Polyox 1105 275.8 — — — — — — — — 224.5Hydroxypropyl — 101.1 — 110.5 — 192.1 — — 140.9 185.6 methyl celluloseSilicon Dioxide 1.3 1.3 1.2 2.4 2.1 3.2 4.0 4.0 2.0 3.8 Magnesium 5.79.4 6.6 5.5 7.7 9.4 6.4 5.2 9.9 7.2 Stearate Formulation No. 21 22 23 2425 26 27 28 29 30 Immediate APAP 185.3 175.0 180.0 160.4 200.0 193.4118.8 162.5 139.0 150.0 Release Oxycodone 1.100 1.75 2.00 2.50 1.25 1.002.75 1.875 1.75 1.875 Layer hydrochloride Microcrystalline 23.0 17.019.0 27.0 16.0 18.0 18.0 14.0 21.0 24.0 cellulose Pregelatinized 0.050.15 0.25 0.10 0.05 0.30 0.20 0.25 0.15 0.20 starch Citric Acid 0.080.08 0.08 0.11 0.11 0.14 0.07 0.13 0.15 0.17 Anhydrous EDTA disodium0.087 0.106 0.075 0.03 0.050 0.055 0.033 0.025 0.045 0.018 salt,dihydrate Hydroxypropyl 14.1 17.8 — — 17.3 — 16.7 16.1 21.5 — celluloseHypromellose 2.5 — 3.2 — — — — — 8.9 19.5 Hydroxypropyl — — 21.7 18.3 —19.3 — — — 3.0 methyl cellulose Croscarmellose 10.0 11.0 11.5 11.5 13.014.5 14.5 12.5 14.0 12.5 sodium Silicon dioxide 0.97 0.75 1.14 1.02 1.101.03 0.88 1.05 0.93 2.30 Magnesium 1.5 1.0 1.0 0.5 0.5 2.0 2.0 0.5 1.52.5 stearate Extended APAP 185.3 150.0 145.0 155.2 125.0 100.5 146.9162.5 207.4 150.0 Release Oxycodone 6.900 5.75 5.50 5.00 6.25 6.50 7.255.625 4.75 6.625 Layer hydrochloride Microcrystalline 175.4 180.0 302.2275.0 214.8 250.0 245.7 203.6 288.3 200.5 cellulose Pregelatinized 0.600.60 0.70 0.70 0.70 0.75 0.75 0.75 0.85 0.85 starch Citric Acid 0.240.16 0.24 0.22 0.33 0.28 0.07 0.38 0.45 0.34 Anhydrous EDTA disodium0.160 0.085 0.095 0.055 0.130 0.065 0.065 0.075 0.130 0.125 salt,dihydrate Hydroxypropyl 30.0 275.8 95.5 210.6 13.2 40.7 32.9 9.6 — —cellulose Polyox N60K 292.8 — — — 287.7 — — — 155.5 — Polyox 205 — —244.2 — — — 275.5 321.8 — 189.2 Hydroxypropyl — 103.2 — 134.2 — 182.2 —— 155.5 210.2 methyl cellulose Silicon Dioxide 1.8 1.3 1.5 2.3 2.4 3.03.5 3.6 2.0 2.5 Magnesium 7.5 8.0 7.4 8.1 7.5 10.2 9.9 7.2 10.3 10.3Stearate Formulation No. 31 32 33 34 35 36 37 38 39 40 Immediate APAP300.0 150.0 200.0 150.0 100.0 160.0 190.0 75.0 90.0 125.0 ReleaseOxycodone 2.00 1.00 1.50 3.50 2.75 1.25 1.25 2.50 1.75 3.00 Layerhydrochloride Microcrystalline 21.5 18.5 25.3 35.0 15.7 27.1 9.9 13.924.2 16.9 cellulose Pregelatinized 0.03 0.30 0.25 0.27 0.08 0.35 0.750.09 0.15 0.26 starch Citric Acid 0.12 0.08 0.09 0.16 0.07 0.24 0.140.26 0.15 0.20 Anhydrous EDTA disodium 0.04 0.175 0.1 0.06 0.1 0.09 0.060.08 0.063 0.09 salt, dihydrate Hydroxypropyl — 21.5 1.8 9.8 14.8 — 20.819.2 25.4 — cellulose Hypromellose 2.5 — — — — — — — 10.3 22.5Hydroxypropyl 16.3 11.4 17.5 8.7 — 29.3 — — — 4.4 methyl celluloseCroscarmellose 6.8 11.0 12.8 7.9 19.0 9.6 13.3 15.6 15.1 14.7 sodiumSilicon dioxide 0.86 0.80 2.25 1.24 .95 1.34 0.80 1.66 0.79 2.37Magnesium 1.75 1.0 0.75 0.6 0.5 2.5 1.9 0.8 1.2 2.8 stearate ExtendedAPAP 150.0 150.0 125.0 75.0 100.0 165.0 135.0 225.0 210.0 150.0 ReleaseOxycodone 8.00 6.50 6.00 6.50 3.25 6.25 6.25 5.00 6.25 5.50 Layerhydrochloride Microcrystalline 182.2 197.6 300.4 269.6 210.0 275.5 283.2310.2 240.8 210.0 cellulose Pregelatinized 0.75 0.73 0.46 0.89 0.55 0.780.55 0.65 0.67 0.64 starch Citric Acid 0.25 0.36 0.38 0.34 0.37 0.230.14 0.40 0.70 0.70 Anhydrous EDTA disodium 0.23 0.09 0.14 0.06 0.1830.035 0.049 0.03 0.105 0.075 salt, dihydrate Hydroxypropyl 34.7 321.988.4 212.9 11.9 37.7 34.2 17.4 — — cellulose Polyox N60K — 45.5 249.924.3 282.0 49.8 200.1 240.1 186.8 — Polyox 205 268.4 — 53.6 70.2 — —36.3 10.4 — 259.3 Hydroxypropyl — 90.5 — 65.4 — 192.1 — — 127.3 142.0methyl cellulose Silicon Dioxide 1.3 1.3 1.2 2.4 2.1 3.2 4.0 4.0 2.0 3.8Magnesium 5.7 9.4 6.6 5.5 7.7 9.4 6.4 5.2 9.9 7.2 Stearate FormulationNo. 41 42 43 44 45 46 47 48 49 50 Immediate APAP 185.3 175.0 180.0 160.4200.0 193.4 118.8 162.5 139.0 150.0 Release Oxycodone 1.100 1.75 2.002.50 1.25 1.00 2.75 1.875 1.75 1.875 Layer hydrochlorideMicrocrystalline 23.0 17.0 19.0 27.0 16.0 18.0 18.0 14.0 21.0 24.0cellulose Pregelatinized 0.05 0.15 0.25 0.10 0.05 0.30 0.20 0.25 0.150.20 starch Citric Acid 0.08 0.08 0.08 0.11 0.11 0.14 0.07 0.13 0.150.17 Anhydrous EDTA disodium 0.087 0.106 0.075 0.03 0.050 0.055 0.0330.025 0.045 0.018 salt, dihydrate Hydroxypropyl 14.1 17.8 — — 17.3 —16.7 16.1 21.5 — cellulose Hypromellose 2.5 — 3.2 — — — — — 8.9 19.5Hydroxypropyl — — 21.7 18.3 — 19.3 — — — 3.0 methyl celluloseCroscarmellose 10.0 11.0 11.5 11.5 13.0 14.5 14.5 12.5 14.0 12.5 sodiumSilicon dioxide 0.97 0.75 1.14 1.02 1.10 1.03 0.88 1.05 0.93 2.30Magnesium 1.5 1.0 1.0 0.5 0.5 2.0 2.0 0.5 1.5 2.5 stearate Extended APAP185.3 150.0 145.0 155.2 125.0 100.5 146.9 162.5 207.4 150.0 ReleaseOxycodone 6.900 5.75 5.50 5.00 6.25 6.50 7.25 5.625 4.75 6.625 Layerhydrochloride Microcrystalline 175.4 180.0 302.2 275.0 214.8 250.0 245.7203.6 288.3 200.5 cellulose Pregelatinized 0.60 0.60 0.70 0.70 0.70 0.750.75 0.75 0.85 0.85 starch Citric Acid 0.24 0.16 0.24 0.22 0.33 0.280.07 0.38 0.45 0.34 Anhydrous EDTA disodium 0.160 0.085 0.095 0.0550.130 0.065 0.065 0.075 0.130 0.125 salt, dihydrate Hydroxypropyl 30.0275.8 95.5 210.6 13.2 40.7 32.9 9.6 — — cellulose Polyox N-750 292.8 — —— 287.7 — — — 155.5 — Polyox 301 — — 244.2 — — — 275.5 321.8 — 189.2Hydroxypropyl — 103.2 — 134.2 — 182.2 — — 155.5 210.2 methyl celluloseSilicon Dioxide 1.8 1.3 1.5 2.3 2.4 3.0 3.5 3.6 2.0 2.5 Magnesium 7.58.0 7.4 8.1 7.5 10.2 9.9 7.2 10.3 10.3 Stearate Formulation No. 51 52 5354 55 56 57 58 59 60 Immediate APAP 300.0 150.0 200.0 150.0 100.0 160.0190.0 75.0 90.0 125.0 Release Oxycodone 2.00 1.00 1.50 3.50 2.75 1.251.25 2.50 1.75 3.00 Layer hydrochloride Microcrystalline 21.5 18.5 25.335.0 15.7 27.1 9.9 13.9 24.2 16.9 cellulose Pregelatinized 0.03 0.300.25 0.27 0.08 0.35 0.75 0.09 0.15 0.26 starch Citric Acid 0.12 0.080.09 0.16 0.07 0.24 0.14 0.26 0.15 0.20 Anhydrous EDTA disodium 0.040.175 0.1 0.06 0.1 0.09 0.06 0.08 0.063 0.09 salt, dihydrateHydroxypropyl — 21.5 1.8 9.8 14.8 — 20.8 19.2 25.4 — celluloseHypromellose 2.5 — — — — — — — 10.3 22.5 Hydroxypropyl 16.3 11.4 17.58.7 — 29.3 — — — 4.4 methyl cellulose Croscarmellose 6.8 11.0 12.8 7.919.0 9.6 13.3 15.6 15.1 14.7 sodium Silicon dioxide 0.86 0.80 2.25 1.24.95 1.34 0.80 1.66 0.79 2.37 Magnesium 1.75 1.0 0.75 0.6 0.5 2.5 1.9 0.81.2 2.8 stearate Extended APAP 150.0 150.0 125.0 75.0 100.0 165.0 135.0225.0 210.0 150.0 Release Oxycodone 8.00 6.50 6.00 6.50 3.25 6.25 6.255.00 6.25 5.50 Layer hydrochloride Microcrystalline 182.2 197.6 300.4269.6 210.0 275.5 283.2 310.2 240.8 210.0 cellulose Pregelatinized 0.750.73 0.46 0.89 0.55 0.78 0.55 0.65 0.67 0.64 starch Citric Acid 0.250.36 0.38 0.34 0.37 0.23 0.14 0.40 0.70 0.70 Anhydrous EDTA disodium0.23 0.09 0.14 0.06 0.183 0.035 0.049 0.03 0.105 0.075 salt, dihydrateHydroxypropyl 34.7 321.9 88.4 212.9 11.9 37.7 34.2 17.4 — — cellulosePolyox N-750 63.4 30.1 125.9 100.3 149.2 63.2 150.5 140.3 94.3 — Polyox301 210.4 — 175.8 60.7 175.8 — 160.5 149.7 100.8 194.6 Hydroxypropyl —128.3 — 65.4 — 227.7 — — 127.3 142.0 methyl cellulose Silicon Dioxide1.3 1.3 1.2 2.4 2.1 3.2 4.0 4.0 2.0 3.8 Magnesium 5.7 9.4 6.6 5.5 7.79.4 6.4 5.2 9.9 7.2 Stearate

CHART 2 Additional Oxycodone/Acetaminophen Formulations. 61 62 63 64 6566 67 68 69 70 Immediate APAP 250.0 250.0 250.0 250.0 250.0 250.0 325.0325.0 162.5 162.5 Release Oxycodone hydrochloride 3.75 3.75 3.75 7.5 7.57.5 3.75 3.75 2.5 3.75 Layer Microcrystalline cellulose 23.72 23.7223.72 32.42 32.42 32.42 28.10 28.10 15.50 18.40 Pregelatinized starch0.50 0.50 0.50 1.00 1.00 1.00 0.50 0.50 0.33 0.50 Citric Acid Anhydrous0.25 0.25 0.25 0.50 0.50 0.50 0.25 0.25 0.17 0.25 EDTA disodium salt,0.05 0.05 0.05 0.10 0.10 0.10 0.05 0.05 0.033 0.05 dihydrateHydroxypropyl cellulose 25.23 25.23 25.23 26.43 26.43 26.43 32.24 32.2316.32 16.72 Croscarmellose sodium 19.21 19.21 19.21 20.13 20.13 20.1312.09 25.087 12.70 13.01 Silicon dioxide 1.63 1.63 1.63 1.70 1.70 1.702.09 2.09 1.06 1.08 Magnesium stearate 0.81 0.81 0.81 0.85 0.85 0.851.045 1.045 0.53 0.54 Extended APAP 250.0 250.0 250.0 250.0 250.0 250.0325.0 325.0 162.5 162.5 Release Oxycodone hydrochloride 11.25 11.2511.25 22.5 22.5 22.5 11.25 11.25 7.5 11.25 Layer Microcrystallinecellulose 175.24 103.74 103.74 159.62 88.12 88.12 23.85 23.85 201.02195.80 Pregelatinized starch 1.50 1.50 1.50 3.00 3.00 3.00 1.50 1.501.00 1.50 Citric Acid Anhydrous 0.75 0.75 0.75 1.50 1.50 1.50 0.75 0.750.50 0.75 EDTA disodium salt, 0.15 0.15 0.15 0.30 0.30 0.30 0.15 0.150.10 0.15 dihydrate Hydroxypropyl cellulose 15.13 15.13 15.13 17.1117.11 17.11 — 19.16 9.91 10.57 Polyox 1105 250.25 321.75 — 250.25 321.75— 321.02 321.02 321.75 321.75 Polyox N60K — — 321.75 — — 321.75 — — — —Silicon Dioxide 3.58 3.58 3.58 3.58 3.58 3.58 3.57 3.57 3.58 3.58Magnesium Stearate 7.15 7.15 7.15 7.15 7.15 7.15 7.13 7.13 7.15 7.15*All weights in mg.

III. Methods for Preparing Solid Dosage Forms of the PharmaceuticalComposition

Another aspect of the disclosure provides methods for preparing soliddosage forms of the pharmaceutical composition that provide extendedrelease of oxycodone and acetaminophen. Solid dosage compositions in theform of tablets may be produced using any suitable method known in theart including but not limited to wet granulation, dry granulation,direct compression, and combinations thereof.

Granulation is a manufacturing process which increases the size andhomogeneity of active pharmaceutical ingredients and excipients thatcomprise a solid dose composition. The granulation process, which isoften referred to as agglomeration, changes important physicalcharacteristics of the dry composition, with the aim of improvingmanufacturability and, thereby, product quality, as well as providingdesired release kinetics. Wet granulation is by far the more prevalentagglomeration process utilized within the pharmaceutical industry. Mostwet granulation procedures follow some basic steps; the active agent(s)and excipients are mixed together, and a binder solution is prepared andadded to the powder mixture to form a wet mass. The moist particles arethen dried and sized by milling or by screening through a sieve. In somecases, the wet granulation is “wet milled” or sized through screensbefore the drying step. The wet granulation process may be a high sheargranulation process or a fluid bed granulation process. Several methodsof granulation are described in co-pending application U.S. applicationSer. No. 13/166,770, filed Jun. 22, 2011, which is incorporated hereinby reference in its entirety.

After granulation and drying of the resultant particles, batches arecharacterized with respect to properties such as final Loss on Drying(LOD), bulk density, tap density, and particle size. Loss on Drying(LOD) typically is determined after each granulation using the MoistureAnalyzer. Several 1 g samples may be taken and loaded into the moistureanalyzer. The samples may be run for 5 minutes at a temperature of 105°C. In another embodiment, the samples may be run at 105° C. until thereis no weight fluctuation in order to determine the LOD.

Bulk and tap densities may be determined as follows. A graduatedcylinder is filled with a certain amount of material (e.g., 30-40 g or82-88 g), and the volume recorded to determine the material bulkdensity. Tap density can be determined with a help of a Tap DensityTester by exposing the material to 100 taps per test and recording thenew volume.

Particle size determination generally is performed immediately aftergranulation, after sieving through 20 mesh screen to removeagglomerates. Particle diameter may be determined with a sieve-typeparticle diameter distribution gauge using sieves with openings of 30,40, 60, 80, 120, and 325 mesh. Fractions may be weighed on a Mettlerbalance to estimate size distribution. This provides determination ofthe quantitative ratio by particle diameter of composition comprisingextended release particles. Sieve analysis according to standard UnitedStates Pharmacopoeia methods (e.g., USP-23 NF 18), may be done such asby using a Meinzer II Sieve Shaker.

In one embodiment, the method for preparing dosage forms of thepharmaceutical composition may comprise wet granulating a first mixturecomprising oxycodone, acetaminophen, and a binder to produce a firstgranulation mixture. The wet granulation process may be a fluid bedgranulation process. In additional embodiments, the first mixture mayfurther comprise at least one additional excipient selected from thegroup consisting of fillers, lubricants, antioxidants, chelating agents,and color agents. The first granulation mixture may be blended with anextended release polymer and one or more excipients, as listed above, toform at least one extended release portion of a dosage form. In certainembodiments, the extended release polymer may be a polyethylene oxide.

In another embodiment, the method further comprises wet granulating asecond mixture comprising oxycodone, acetaminophen, and a binder to forma second granulation mixture. The wet granulation process may be a fluidbed granulation process. In some embodiments, the second mixture mayfurther comprise at least one additional excipient selected from thegroup consisting of fillers, lubricants, disintegrants, antioxidants,chelating agents, and color agents. The second granulation mixture maybe blended with one or more excipients, as listed above, to form animmediate release portion of a dosage form.

In an additional embodiment, the method may further comprise compressingthe at least one extended release portion and the at least one immediaterelease portion into a tablet. The tablet may be a bilayer tablet. Thetablet may be coated with a tablet coating.

In another embodiment, the method may comprise granulating via a highshear wet granulation process a mixture comprising oxycodone and atleast one excipient to form oxycodone particles. The oxycodone particlesmay be dried at a suitable temperature. The oxycodone particlescomprising oxycodone may be granulated via a fluid bed granulationprocess with acetaminophen, a binder, and an optional excipient to formthe granulation mixture. The granulation mixture may be blended with anextended release polymer and at least one excipient to form an extendedrelease portion of a solid dosage form.

In a further embodiment, the method may further comprise granulating viaa fluid bed granulation process oxycodone particles comprising oxycodonewith acetaminophen, a binder, and an optional excipient to form anothergranulation mixture. This granulation mixture may be blended with one ormore excipients to form an immediate release portion of a solid dosageform.

In an additional embodiment, the method may further comprise compressingthe at least one extended release portion comprising oxycodone particlesand the at least one immediate release portion comprising oxycodoneparticles into a tablet. In one embodiment, the method comprisescompressing one extended release portion comprising the oxycodoneparticles and one immediate release portion comprising the oxycodoneparticles into a bilayer tablet. The tablet may be coated with a tabletcoating.

In another embodiment, wet granulation of either mixture may produceparticles with a bulk density ranging from about 0.30 to 0.40grams/milliliter (g/mL). In other aspects, the wet granulation mayproduce particles with a tap density ranging from about 0.35 g/mL toabout 0.45 g/mL. In other embodiments, the wet granulation may produceparticles, wherein at least about 50% of the particles have a sizegreater than 125 microns. In still other embodiments, the wetgranulation may produce particles wherein about 20% to about 65% of theparticles have a size greater than about 125 microns and less than about250 microns.

Tablets generally are characterized with respect to disintegration anddissolution release profiles as well as tablet hardness, friability, andcontent uniformity.

In vitro dissolution profiles for the tablets may be determined using aUSP Type II apparatus, with a paddle speed of either about 100 rpm or150 rpm, in 0.1 N HCl, at 37° C. Samples of 5 ml at each time-point maybe taken without media replacement at 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and12 hours, for example. In some embodiments, the dissolution profiles maybe determined at varying pH values, such as at a pH of about 3.0, 3.5,4.0, 4.5, 5.0, 5.5, 6.0 or 6.5. The fluid used may be, for example, HCl,phosphate buffer, or simulated gastric fluid. The resulting cumulativedissolution profiles for the tablets are based upon a theoreticalpercent active added to the compositions.

A tablet preferably disintegrates before it dissolves. A disintegrationtester measures the time it takes a tablet to break apart in solution.The tester suspends tablets in a solution bath for visual monitoring ofthe disintegration rate. Both the time to disintegration and thedisintegration consistency of all tablets may be measured. Thedisintegration profile may be determined in a USP Disintegration Testerin 0.1 N HCl of pH 1.2. The fluid used may be, for example, HCl,phosphate buffer, or simulated gastric fluid. Samples, 1-5 ml at eachtime-point, may be taken, for example, without media replacement at 0.5,1, 2, 3, 4, 5, 6, 7 and 8 hours. The resulting cumulative disintegrationprofiles are based upon a theoretical percent active added to thepharmaceutical compositions.

After tablets are formed by compression, it is desired that the tabletshave a strength of at least 9-25 Kiloponds (kp), or at least about 12-20kp. A hardness tester generally is used to determine the load requiredto diametrically break the tablets (crushing strength) into two equalhalves. The fracture force may be measured using a Venkel TabletHardness Tester, using standard USP protocols.

Friability is a well-known measure of a tablet's resistance to surfaceabrasion that measures weight loss in percentage after subjecting thetablets to a standardized agitation procedure. Friability properties areespecially important during any transport of the dosage form as anyfracturing of the final dosage form may result in a subject receivingless than the prescribed medication. Friability may be determined usinga Roche Friability Drum according to standard USP guidelines whichspecifies the number of samples, the total number of drum revolutions,and the drum rpm to be used. Friability values of from 0.8 to 1.0%generally are regarded as constituting the upper limit of acceptability.

The prepared tablets generally are tested for content uniformity todetermine if they meet the pharmaceutical requirement of an acceptancevalue of 15 or less. Each tablet may be placed in a solution of 60%methanol/40% isopropanol and stirred at room temperature until thetablet disintegrates. The solution containing the dissolved tablet maybe further diluted in 90% water/10% isopropanol/0.1% heptafluorobutyricacid and generally is analyzed by HPLC.

IV. Method for Reducing the Risk of Acetaminophen-Induced Hepatic Damage

The present disclosure also provides methods for reducing the risk ofacetaminophen-induced hepatic damage in a subject being treated for painwith a dosage regimen that comprises administering to the subject atleast two consecutive doses of a pharmaceutical composition comprisingoxycodone and acetaminophen. The method comprises administering a firstdose of a pharmaceutical composition comprising at least one extendedrelease portion comprising the acetaminophen, the oxycodone or acombination thereof, and an extended release component to the subject,wherein the composition maintains a therapeutic blood plasmaconcentration of oxycodone of at least 5 ng/mL from about 0.75 hours toabout 10 hours after administration of the composition, and wherein atleast about 90% of the acetaminophen is released from the composition byabout 8 hours after administration of the composition such that, byabout 10 hours after administration of the composition, acetaminophenhas a blood plasma concentration that is less than about 30% ofacetaminophen's maximum plasma concentration. The method furthercomprises administering a second dose of the pharmaceutical compositionto the subject at about 12 hours after administration of the first dose.

Avoiding toxic intermediate formation is an important strategy inaddressing product safety. Indeed, acetaminophen is absorbed from thestomach and small intestine and primarily metabolized by conjugation inthe liver to nontoxic, water-soluble compounds that are eliminated inthe urine. When the maximum daily dose (“MDD”) is exceeded over aprolonged period, metabolism by conjugation becomes saturated, andexcess acetaminophen is oxidatively metabolized by the CYP enzymes(CYP2E1, 1A2, 2A6, 3A4) to a reactive metabolite,N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely shorthalf-life, and rapidly conjugates with available glutathione, which actsas a sulfhydryl donor. The reduced NAPQI is then renally excreted. Theliver plays a central role in the turnover of glutathione in the body.Given that toxicity due to NAPQI formation occurs via necrosis of theliver following the formation of toxic adducts, minimizing glutathionedepletion and enhancing glutathione regeneration in the liver is animportant concern.

Human erythrocyte data resulting from hepatic turnover demonstrate atime-delayed response to redox and free radical insults via glutathionedepletion and regeneration. The hepatic dynamics of glutathioneformation and depletion in animal data using hepatic models can also bereviewed. In Swiss mice, the dynamics of glutathione depletion wasinvestigated in detail for acetaminophen doses ranging from (100 mg/kgto 600 mg/kg) in work done by Brzeznicka and Piotrowski (1989). Underone embodiment of the present invention, the intended dosage forpatients with acute pain is 1.3 g/day of acetaminophen. Assuming asubject's weight of 70 kg, this is 1.229×10⁻⁴ moles/kg/day in humansubjects. In Swiss mice, 400 mg/kg and 600 mg/kg are 2.65×10⁻³moles/kg/day and 3.97×10⁻³ moles/kg/day, respectively, resulting in a22-fold and a 32-fold safety exposure ratio, as compared with humanlevels. The bioequivalence level is 95%. Brzeiznicka and Piotrowskireport that circulating hepatic GSH changes in mice began within 15 minafter acetaminophen administration, and depletion followed a patternthat was strictly dose dependent, reaching a minimum GSH level 2 hrsafter injection for the all dose groups, rebounding to initial levelsbetween hours 8 and 12. Taken together, these results support thehypothesis that exposing subjects to the lower end of the therapeuticwindow of acetaminophen may provide benefit in terms of the patient'sability to regenerate physiologically protective levels of glutathione.Thus, the pharmaceutical formulations disclosed herein, which aredesigned to allow for a two hour break in acetaminophen exposure in eachtwelve hour exposure window allows for restorative hepatic regenerationof the subject's glutathione levels during that period when theacetaminophen concentrations are at their lowest or absent, while stillpreserving the considerable benefits of the potentiating effects ofcombination analgesia.

As mentioned above, acetaminophen is primarily metabolized viaconjugation reactions, e.g., glucuronidation and sulfation, in the liverto nontoxic, water-soluble compounds that are rapidly eliminated fromthe body. A small proportion of acetaminophen is metabolized by thecytochrome P450 system to the reactive metabolite, NAPQI. Generally,this toxic metabolite is rapidly detoxified by conjugation toglutathione to form a non-toxic metabolite that is renally excreted.However, if the conjugation pathways become saturated and moreacetaminophen is metabolized via the cytochrome P450 pathway, the poolof available glutathione may become depleted. With insufficientglutathione to bind to and inactivate NAPQI, this toxic metabolite isable to react with the sulfhydryl groups of cellular proteins initiatinga cascade of cellular damage, which may lead to liver necrosis, and,ultimately, liver failure.

The method disclosed herein addresses the problem of depleted stores ofglutathione by providing a period of time during the later part of thedosing interval during which the release of acetaminophen is low becausemost of the acetaminophen has already been released from thecomposition. The period of time during which the release ofacetaminophen is low is called the acetaminophen “time-off” period. As aconsequence of this acetaminophen time-off period, the plasma levels ofacetaminophen fall to sufficiently low levels such that the metabolicburden on the liver is reduced, thereby allowing the depleted stores ofglutathione to be replenished via the continuous glutathionemanufacturing pathway comprising the glutathione synthase pathway.Because the levels of glutathione are able to be restored before thenext dose, the risk of acetaminophen-induced hepatic damage issignificantly reduced.

Additionally, the acetaminophen time-off period provided by thecompositions disclosed herein may provide an added and beneficialprecaution for any subject undergoing acetaminophen therapy to avoid aninadvertent reduction in glutathione stores and any potentialacetaminophen-induced hepatic damage. In particular, the acetaminophentime-off period provided by the compositions disclosed herein may beespecially useful during chronic administration of analgesiccompositions comprising acetaminophen. The subject may be at increasedrisk for developing acetaminophen-induced hepatic damage because offrequent and regular user of alcohol (i.e., ethanol), concurrentadministration of acetaminophen from another source (e.g., anover-the-counter medication), poor diet, and/or compromised liverfunction.

In general, the compositions disclosed herein are formulated such thatthe rate of release of acetaminophen is high during the first severalhours of the dosing interval and the rate of release of acetaminophen islow during the last several hours of the dosing interval. Morespecifically, the compositions are formulated to release from about 40%to about 65% of the acetaminophen in about 30 minutes, from about 55% toabout 80% of the acetaminophen in about 2 hours, from about 65% to about92% of the acetaminophen in about 4 hours, and from about 67% to about95% of the acetaminophen in about 8 hours, wherein the dosing intervalis about 12 hours. In another, the compositions are formulated torelease from about 45% to about 60% of the acetaminophen in about 30minutes, from about 57% to about 75% of the acetaminophen in about 2hours, from about 67% to about 90% of the acetaminophen in about 4hours, and from about 70% to about 95% of the acetaminophen in about 8hours, wherein the dosing interval is about 12 hours. In yet anotherembodiment, during the final 4 hours of a 12 hour dosing interval, onlyabout 5% of the acetaminophen remains to be released from thecomposition.

The subject may be a mammal, and in certain embodiments, the subject maybe a human. In various embodiments, the at least two consecutive dosesof the analgesic composition may be administered to the subject at 8hour intervals, 10 hour intervals, 12 hour intervals, 18 hour intervals,or 24 hour intervals.

The method for reducing the risk of acetaminophen-induced hepatic damagedisclosed herein may further comprise administering additional doses ofthe pharmaceutical composition at regular dosing intervals, such ase.g., at 12 hour intervals. During the latter part of each dosinginterval, therefore, the acetaminophen time-off period allows depletedstores of glutathione to be replenished, thereby reducing the risk ofacetaminophen-induced hepatic damage in subjects being treated for painwith a composition comprising acetaminophen.

V. Method for Treating Pain

Also provided is a method for treating pain in a subject in need of suchtreatment with a pharmaceutical composition that comprises oxycodone andacetaminophen, wherein the method comprises administering an effectiveamount of any of the pharmaceutical compositions disclosed herein. Themethod comprises orally administering to the subject an effective amountof a pharmaceutical composition comprising at least one extended releaseportion comprising oxycodone, acetaminophen and combination thereof, andan extended release component, wherein the composition maintains atherapeutic plasma concentration of oxycodone of at least about 5 ng/mLfrom about 0.75 hour to about 10 hours after administration of thecomposition, and wherein at least about 90% of the acetaminophen isreleased from the composition by about 8 hours after administration ofthe composition such that, by about 10 hours after administration of thecomposition, acetaminophen has a blood plasma concentration that is lessthan about 30% of acetaminophen's maximum plasma concentration.

In some embodiments, the subject may be suffering from or diagnosed withchronic pain. In yet another embodiment, the subject may be sufferingfrom or diagnosed with acute pain. In still another embodiment, thesubject may be suffering from or diagnosed with moderate to severe acutepain. In yet other embodiments, the subject may be suffering from ordiagnosed with both chronic and acute pain. The subject may be a mammal,and in certain embodiments, the subject may be a human.

In one embodiment, the effective amount of a pharmaceutical compositionmay be 15 mg of oxycodone and 650 mg of acetaminophen. For example, onesolid dosage form comprising 15 mg of oxycodone and 650 mg ofacetaminophen may be administered. Alternatively, two solid dosage formswith each comprising 7.5 mg of oxycodone and 325 mg of acetaminophen maybe administered. In another embodiment, the effective amount of apharmaceutical composition may be 7.5 mg of oxycodone and 325 mg ofacetaminophen, wherein one solid dosage form comprising 7.5 mg ofoxycodone and 325 mg of acetaminophen may be administered. In yetanother embodiment, the effective amount of a pharmaceutical compositionmay be 20 mg of oxycodone and 650 mg of acetaminophen. For example, onesolid dosage form comprising 20 mg of oxycodone and 650 mg ofacetaminophen may be administered. Alternatively, two solid dosage formswith each comprising 10 mg of oxycodone and 325 mg of acetaminophen maybe administered. In another embodiment, the effective amount of apharmaceutical composition may be 10 mg of oxycodone and 325 mg ofacetaminophen, wherein one solid dosage form comprising 10 mg ofoxycodone and 325 mg of acetaminophen may be administered. In still yetanother embodiment, the effective amount of a pharmaceutical compositionmay be 30 mg of oxycodone and 650 mg of acetaminophen. For example, onesolid dosage form comprising 30 mg of oxycodone and 650 mg ofacetaminophen may be administered. Alternatively, two solid dosage formswith each comprising 15 mg of oxycodone and 325 mg of acetaminophen maybe administered. In another embodiment, the effective amount of apharmaceutical composition may be 15 mg of oxycodone and 325 mg ofacetaminophen, wherein one solid dosage form comprising 15 mg ofoxycodone and 325 mg of acetaminophen may be administered.

The dosing intervals of the effective amount of the pharmaceuticalcomposition can and will vary. For example, an effective amount of thepharmaceutical composition may be administered once a day, twice a day,or three times a day. In another embodiment, an effective amount of thepharmaceutical composition may be administered twice a day.

In general, therapeutic plasma concentrations of oxycodone andacetaminophen are attained within about 5 minutes, 10 minutes, 15minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45minutes, 50 minutes, 55 minutes, or 60 minutes after administration ofthe first dose of the pharmaceutical composition. Accordingly, dependingupon the severity of the pain, onset on analgesia may be attained withinabout 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or60 minutes after administration of the composition. Onset of analgesiamay be measured by the double stopwatch method or other pain assessmentsas described in Example 12 below. Generally, analgesia or pain reliefwill be maintained throughout the duration of the dosing interval. Forexample, in one embodiment, analgesia or pain relief will be maintainedfor 12 hours. Upon administration of the next dose of the pharmaceuticalcomposition, therefore, analgesia or pain relief may be maintained.Accordingly, analgesia or pain relief will be maintained as long astherapeutic amounts of the pharmaceutical composition are administeredat regular dosing intervals. Moreover, pain relief may be managed suchthat no break-through episodes of pain occur.

In some embodiments, an effective amount of the pharmaceuticalcomposition may be administered to a subject in a fed state. In general,a fed state is defined as having consumed food within about 30 min priorto administration of the pharmaceutical composition. The food may be ahigh fat meal, a low fat meal, a high calorie meal, or a low caloriemeal. In other embodiments, an effective amount of the pharmaceuticalcomposition may be administered to a subject in a fasted state. Ingeneral, a fasted state is defined as not having ingested food for atleast 10 hours prior to administration of the pharmaceuticalcomposition. In some embodiments, the pharmaceutical composition may beadministered to a subject who has fasted for at least 10 hours prior tothe first dose and who fasts for at least one hour prior toadministration of subsequent doses. In other embodiments, thepharmaceutical composition may be administered to a subject who hasfasted for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours,7 hours, 8 hours, 9 hours, or 10 hours prior to administration of eachdose.

The method of the present invention is useful for treating numerous painstates that are currently being treated with conventional immediaterelease compositions comprising acetaminophen and oxycodone. These andadditional pain states include, by way of illustration and notlimitation, headache pain, pain associated with migraine, neuropathicpain selected from the group consisting of diabetic neuropathy, HIVsensory neuropathy, post-herpetic neuralgia, post-thoracotomy pain,trigeminal neuralgia, radiculopathy, neuropathic pain associated withchemotherapy, reflex sympathetic dystrophy, back pain, peripheralneuropathy, entrapment neuropathy, phantom limb pain, and complexregional pain syndrome, dental pain, pain associated with a surgicalprocedure and or other medical intervention, bone cancer pain, jointpain associated with psoriatic arthritis, osteoarthritic pain,rheumatoid arthritic pain, juvenile chronic arthritis associated pain,juvenile idiopathic arthritis associated pain, Spondyloarthropathies(such as ankylosing spondylitis (Mb Bechterew) and reactive arthritis(Reiter's syndrome) associated pain), pain associated with psoriaticarthritis, gout pain, pain associated with pseudogout (pyrophosphatearthritis), pain associated with systemic lupus erythematosus (SLE),pain associated with systemic sclerosis (scleroderma), pain associatedwith Behcet's disease, pain associated with relapsing polychondritis,pain associated with adult Still's disease, pain associated withtransient regional osteoporosis, pain associated with neuropathicarthropathy, pain associated with sarcoidosis, arthritic pain, rheumaticpain, joint pain, osteoarthritic joint pain, rheumatoid arthritic jointpain, juvenile chronic arthritis associated joint pain, juvenileidiopathic arthritis associated joint pain, Spondyloarthropathies (suchas ankylosing spondylitis (Mb Bechterew) and reactive arthritis(Reiter's syndrome) associated joint pain), gout joint pain, joint painassociated with pseudogout (pyrophosphate arthritis), joint painassociated with systemic lupus erythematosus (SLE), joint painassociated with systemic sclerosis (scleroderma), joint pain associatedwith Behcet's disease, joint pain associated with relapsingpolychondritis, joint pain associated with adult Still's disease, jointpain associated with transient regional osteoporosis, joint painassociated with neuropathic arthropathy, joint pain associated withsarcoidosis, arthritic joint pain, rheumatic joint pain, acute pain,acute joint pain, chronic pain, chronic joint pain, inflammatory pain,inflammatory joint pain, mechanical pain, mechanical joint pain, painassociated with the fibromyalgia syndrome (FMS), pain associated withpolymyalgia rheumatica, monarticular joint pain, polyarticular jointpain, nociceptive pain, psychogenous pain, pain of unknown etiology,pain mediated by IL-6, IL-6 soluble receptor, or IL-6 receptor, painassociated with a surgical procedure in a patient with a clinicaldiagnosis of OA, pain like static allodynia, pain like dynamicallodynia, and/or pain associated with Crohn's disease.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

EXAMPLES

The following examples are included to demonstrate certain embodimentsof the invention. Those of skill in the art should, however, in light ofthe present disclosure, appreciate that modifications can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1 In Vitro Dissolution of Controlled-Release Bilayer Tablets

Control-release bilayer tablets were prepared containing 15 mg ofoxycodone and 500 mg of acetaminophen (APAP), or 30 mg of oxycodone and500 mg APAP. (See selected examples from Chart No. 2.) The ER layercontained 75% of the total amount of oxycodone in the tablet, 50% of thetotal amount of APAP in the tablet, and either 35% w/w POLYOX® 1105 (forfast release), 45% w/w POLYOX® 1105 (for medium release), or 45% w/wPOLYOX® N60K (for slow release). The IR layer contained 25% of the totalamount of oxycodone in the tablet and 50% of the total amount of APAP inthe tablet.

Dissolution profiles for the three above-described compositions weredetermined in USP Type II apparatus. Six tablets of each compositionwere weighed, placed in a sinker, and dropped into an equilibrateddissolution bath vessel that contained 900 mL of (helium sparged) 0.1 NHCl that was heated to 37° C.±0.5° C. The mixture was stirred at 150±6rpm and the temperature was maintained at 37° C.±0.5° C. for 12 hr. Thebath vessel was covered with a low evaporation vessel cover. Samples (5mL) were removed at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours. Each samplewas filtered through a 0.45 μm filter and analyzed by HPLC usingstandard procedures.

The cumulative release of oxycodone and APAP from 15 mg oxycodone/500 mgAPAP tablets is presented in Table 1. Table 2 presents the cumulativerelease of oxycodone and APAP from 30 mg oxycodone/500 mg APAP (30/500)tablets. FIG. 1 presents the release profile of oxycodone from the15/500 and 30/500 tablets. The dissolution profile of APAP from the15/500 and 30/500 tablets is shown in FIG. 2. The release of oxycodoneand APAP from the fast release and medium release tablets wasessentially linear during the first half of the 12 hour time period butthen plateaued during the last half of the 12 hour time period. Therelease of oxycodone and APAP from the slow release tablets wasessentially linear during the entire 12 hour time period.

TABLE 1 Cumulative Release- 15 mg oxycodone/500 mg APAP TabletsOxycodone (%) APAP (%) Time (hr) Fast Medium Slow Fast Medium Slow 0.2527.56 25.70 25.68 54.78 53.06 53.01 0.5 34.33 31.31 30.39 57.55 55.7354.89 1.0 — 40.85 37.81 — 60.03 58.03 2.0 59.88 55.67 49.50 71.42 68.1663.27 4.0 83.46 77.94 67.43 86.17 81.55 72.31 6.0 97.48 92.12 80.5396.19 91.62 79.97 8.0 101.26 99.26 90.20 100.16 96.96 86.06 12.0 101.57101.23 99.36 100.10 99.16 94.41

TABLE 2 Cumulative Release- 30 mg oxycodone/500 mg APAP TabletsOxycodone (%) APAP (%) Time (hr) Fast Medium Slow Fast Medium Slow 0.2531.65 30.27 29.78 54.17 52.97 52.97 0.5 37.55 35.91 34.42 56.96 55.6454.97 1.0 47.18 45.21 41.12 61.81 60.19 58.15 2.0 62.51 59.63 52.4070.60 68.04 63.61 4.0 84.72 80.44 70.01 85.28 81.56 73.04 6.0 96.9793.98 82.49 94.57 91.42 80.94 8.0 100.23 99.63 91.78 97.91 96.48 87.2612.0 100.57 101.13 99.60 98.09 98.14 95.25

The cumulative in vitro release of oxycodone and APAP from 7.5 mgoxycodone/325 mg APAP medium release tablets is presented in Table 3.The ER layer of these tablets contained 5.625 mg of oxycodone, 162.5 mgof APAP, and 45% (w/w) POLYOX® 1105, and the IR layer contained 1.875 mgof oxycodone and 162.5 mg of APAP. (See selected example from Chart 1.)The dissolution profile was determined essentially as described above,except that samples were collected at 0.08 hour (˜5 min) in addition tothe later time points.

TABLE 3 Cumulative Release 7.5 mg oxycodone/325 mg APAP TabletsOxycodone (%) APAP (%) Time Mean % RSD Mean % RSD (hr) (%) (6) (%) (%)0.08 26.6 4.3 49.0 3.4 0.25 31.5 4.2 51.3 3.1 0.5 37.5 2.7 53.8 2.9 1.045.9 1.6 58.2 2.5 2.0 60.1 1.7 66.0 2.3 4.0 81.4 1.1 78.7 1.7 6.0 95.41.4 88.4 1.9 8.0 101.8 0.9 93.9 1.4 12.0 103.2 1.2 94.9 1.1

FIG. 3 and FIG. 4 present the percentage of oxycodone and APAP,respectively, released from two different lots of 7.5/325 tablets ascompared to 15/650 tablets (see Example 28 for the dissolution data ofthe 15 mg oxycodone/650 acetaminophen tablets). The dissolution profileswere similar among all the tablets.

The release of oxycodone and APAP from each layer was analyzed bydetermining the calculated release from the ER layer and actual releasefrom the total composition. For this, the tablets contained 7.5 mg ofoxycodone HCl and 325 mg of APAP (i.e., the ER layer contained 5.625 mgof oxycodone HCl, 162.5 mg of APAP, and 45% (w/w) POLYOX® 1105; and theIR layer contained 1.875 mg of oxycodone HCl and 162.5 mg of APAP). Thedissolution profile was determined essentially as described above. Thecalculated cumulative release of oxycodone HCl from the ER layer and thetotal tablet is presented in Table 4, and the calculated cumulativerelease of APAP from the ER layer and the total tablet is presented inTable 5. These data show that essentially all of the 1.875 mg ofoxycodone HCl in the IR layer was released within about 5 minutes andessentially all of the 162.5 mg of APAP in the IR layer was releasedwithin about 15 minutes.

TABLE 4 Split Release of Oxycodone 7.5 mg oxycodone/ 325 mg APAP TabletsTime Total Total ER ER (hr) (%) (mg) (%) (mg) 0.08 26.6 2.00 2.1 0.120.25 31.5 2.36 8.7 0.49 0.5 37.5 2.81 16.7 0.94 1.0 45.9 3.44 27.9 1.572.0 60.1 4.51 46.8 2.63 4.0 81.4 6.11 75.2 4.23 6.0 95.4 7.16 93.9 5.288.0 101.8 7.64 102.4 5.76 12.0 103.2 7.74 104.3 5.87

TABLE 5 Split Release of APAP 7.5 mg oxycodone/325 mg APAP Tablets TimeTotal Total ER ER (hr) (%) (mg) (%) (mg) 0.08 49.0 159.25 0.0 0.00 0.2551.3 166.73 2.6 4.22 0.5 53.8 174.85 7.6 12.35 1.0 58.2 189.15 16.426.65 2.0 66.0 214.50 32.0 52.00 4.0 78.7 255.78 57.4 93.28 6.0 88.4287.30 76.8 124.80 8.0 93.9 305.18 87.8 142.68 12.0 94.9 308.43 89.8145.93

Example 2 Clinical Pharmacokinetic Analysis of Controlled-Release 15 mgOxycodone/500 mg Acetaminophen Bilayer Tablets—Single Dose

An open-label, single dose, four-period crossover study was conducted toevaluate the pharmacokinetics (PK) and bioavailability of threecontrolled-release bilayer tablets comprising 15 mg oxycodone (OC) and500 mg APAP as compared to a commercially available immediate-releasetablet containing 7.5 mg oxycodone/325 mg acetaminophen. The threecontrolled release formulations—fast, medium, and slow—are describedabove. (See selected examples from Chart No. 2.) One tablet of each ofthe controlled-release bilayer formulations was administered to the testsubjects under fed conditions. One tablet of the commercially availableimmediate-release tablet containing 7.5 mg oxycodone/325 mgacetaminophen was administered every 6 hours (Q6h) for two doses underfed conditions. The test subjects were about 40 normal, healthy malesubjects between 21-45 years of age.

Subjects were randomly assigned to Treatments A, B, C, and D using afour-period, eight-sequence, crossover design as follows:

-   -   Treatment A: One (1) tablet of 15 mg OC/500 mg APAP, Fast        Release administered orally under fed conditions.    -   Treatment B: One (1) tablet of 15 mg OC/500 mg APAP, Medium        Release administered orally under fed conditions.    -   Treatment C: One (1) tablet of 15 mg OC/500 mg APAP, Slow        Release administered orally under fed conditions.    -   Treatment D: One (1) tablet of a commercially available        immediate-release tablet containing 7.5 mg oxycodone/325 mg        administered orally Q6h for two (2) doses under fed conditions.

The crossover design allowed for within-subject comparisons among thetest formulations with differing release profiles. Subjects receivedeach of the study drug treatments (A-D) separated by at least a 7-dayinterval between the start of each period at Hour 0. During each period,subjects remained in the clinical facility from the time of check-in (onthe day prior to dosing) until discharge on Day 3 (after the 48 hourblood draw).

Physical examinations, electrocardiograms and clinical laboratory testswere performed at screening and at the conclusion of the study (or earlytermination). Vital sign measurements (including pulse oximetry) andadverse events were monitored during the study. Subjects wereadministered a 50 mg naltrexone tablet 12 hours prior to Hour 0 dosing,at Hour 0, and 12 hours post-dose to block the effects and potentialrisks of oxycodone. After a 10 hour overnight fast, subjects were serveda standardized FDA high-fat breakfast to be consumed in 30 minutes orless prior to Hour 0 dosing for the first oral dosage. All subjects ineach period were served a standardized meal to be consumed in 30 minutesor less prior to Hour 6. Only subjects randomized to Treatment D wereadministered the second oral dosage of the commercially availableimmediate-release tablet containing 7.5 mg oxycodone/325 mgacetaminophen at Hour 6 in each period.

Blood was drawn at designated times for PK analysis. Samples (6 mL inpre-chilled vacuum blood collection tubes, containing K2EDTA as theanticoagulant) were taken pre-dose (up to 60 minutes prior to dose), 10min, 20 min, 30 min, 40 min and 1, 2, 3, 4, 5, 6, 6.5, 7, 8, 9, 10, 12,16, 18, 20, 24, 36 and 48 hours post-dose. The collected plasma sampleswere analyzed for the active pharmaceutical ingredients (APIs), i.e.,oxycodone and acetaminophen, using validated liquidchromatography/tandem mass spectrometry (LC-MS/MS) assays.

The following PK parameters were calculated for oxycodone andacetaminophen using standard non-compartmental methods:

-   -   area under the plasma concentration curve to last quantifiable        concentration AUC_((0-t))    -   area under the plasma concentration curve to infinite time        AUC_((0-inf))    -   maximum observed plasma concentration (C_(max))    -   time observed maximum plasma concentration (t_(max))    -   lag time (t_(lag))    -   apparent first-order terminal elimination rate constant (k_(el))    -   apparent plasma terminal elimination half-life (t_(1/2))

Parametric general linear model (GLM) methodology was used in theanalysis of all pharmacokinetic parameters. The SAS GLM procedure wasused to perform analysis of variance (ANOVA) on each pharmacokineticparameter with sequence, treatment, period, and subjects nested withinsequences, as sources of variation. For each formulation, least squaresmeans and the associated standard errors were obtained using the LSMEANSoption. All treatment pairwise comparisons were performed, withoutadjustment for multiplicity. AUC and C_(max) were dose-adjusted forcomparative purposes for acetaminophen and the commercially availableimmediate-release tablet containing 7.5 mg oxycodone/325 mgacetaminophen.

The pharmacokinetic data for oxycodone and APAP are presented in Tables6-8 and 9-11, respectively.

TABLE 6 Oxycodone Pharmacokinetics (15/500) Commer- cially availableimmediate- release Fast Release Formulation tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL) 18.803 82.9278.02 88.12 22.428 (21) (20) C_(1hr) (ng/mL) 6.891 72.79 49.02 108.110.226 (77) (65) C_(2hr) ^(a) (ng/mL) 12.355 80.74 71.2 91.56 14.94 (32)(26) AUC_(0-t) 209.949 89.73 86.52 93.06 229.788 (ng · hr/mL) (26) (22)AUC_(0-inf) 211.8 89.95 86.77 93.24 231.421 (ng · hr/mL) (25) (22)AUC_(0-1hr) 2.565 61.32 37.64 99.92 4.334 (ng · hr/mL) (104) (80)AUC_(0-2hr) ^(b) 12.189 70.16 55.97 87.95 16.917 (ng · hr/mL) (53) (46)AUC_(0-4hr) ^(c) 41.3 88.76 80.61 97.73 45.699 (ng · hr/mL) (29) (24)T_(max) (hr) 4.954 na na na 7.954 (34) (22) T_(lag) (hr) 0.31 na na na0.219 (68) (77) T_(1/2) (hr) 4.584 na na na 4.495 (17) (14) K_(el)(1/hr) 0.155 na na na 0.157 (16) (13) ^(a)Concentration at the medianT_(max) for commercially-available immediate release tablet ^(b)AUC fromzero the median T_(max) for commercially-available immediate releasetablet ^(c)AUC from the zero to the median T_(max) + 2SD forcommercially-available immediate release tablet

TABLE 7 Oxycodone Pharmacokinetics (15/500) Commer- cially- availableimmediate release Medium Release Formulation tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL) 18.266 80.8776.09 85.95 22.428 (25) (20) C_(1hr) (ng/mL) 7.364 67.62 45.75 99.9510.226 (81) (65) C_(2hr) ^(a) (ng/mL) 12.388 79.04 69.69 89.64 14.94(45) (26) AUC_(0-t) 217.188 94.19 90.82 97.68 229.788 (ng · hr/mL) (23)(22) AUC_(0-inf) 218.545 94.09 90.77 97.54 231.421 (ng · hr/mL) (23)(22) AUC_(0-1hr) 3.248 64.69 39.93 104.8 4.334 (ng · hr/mL) (118) (80)AUC_(0-2hr) ^(b) 13.124 71.74 57.22 89.96 16.917 (ng · hr/mL) (70) (46)AUC_(0-4hr) ^(c) 42.101 88.61 80.47 97.58 45.699 (ng · hr/mL) (43) (24)T_(max) (hr) 5.31 na na na 7.954 (38) (22) T_(lag) (hr) 0.264 na na na0.219 (64) (77) T_(1/2) (hr) 4.557 na na na 4.495 (16) (14) K_(el)(1/hr) 0.156 na na na 0.157 (16) (13) ^(a)Concentration at the medianT_(max) for commercially-available immediate release tablet ^(b)AUC fromzero the median T_(max) for commercially-available immediate releasetablet ^(c)AUC from the zero to the median T_(max) + 2SD forcommercially-available immediate release tablet

TABLE 8 Oxycodone Pharmacokinetics (15/500) Commer- cially- availableimmediate release Slow Release Formulation tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL) 17.403 76.7572.21 81.58 22.428 (25) (20) C_(1hr) (ng/mL) 7.601 69.63 47.08 102.9710.226 (79) (65) C_(2hr) ^(a) (ng/mL) 11.237 73.55 64.84 83.43 14.94(39) (26) AUC_(0-t) 222.096 95.62 92.2 99.18 229.788 (ng · hr/mL) (25)(22) AUC_(0-inf) 223.553 95.61 92.22 99.11 231.421 (ng · hr/mL) (25)(22) AUC_(0-1hr) 2.893 57.34 35.37 92.95 4.334 (ng · hr/mL) (112) (80)AUC_(0-2hr) ^(b) 12.312 68.63 54.72 86.08 16.917 (ng · hr/mL) (66) (46)AUC_(0-4hr) ^(c) 38.842 83.46 75.78 91.92 45.699 (ng · hr/mL) (35) (24)T_(max) (hr) 5.655 na na na 7.954 (27) (22) T_(lag) (hr) 0.299 na na na0.219 (74) (77) T_(1/2) (hr) 4.647 na na na 4.495 (19) (14) K_(el)(1/hr) 0.154 na na na 0.157 (18) (13) ^(a)Concentration at the medianT_(max) for commercially-available immediate release tablet ^(b)AUC fromzero the median T_(max) for commercially-available immediate releasetablet ^(c)AUC from the zero to the median T_(max) + 2SD forcommercially-available immediate release tablet

TABLE 9 Acetaminophen Pharmacokinetics (15/500) Commer- cially-available immediate release Fast Release Formulation tablet* Mean LSM90% Cl Mean Parameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL)2612 94.46 87.25 102.26 2721 (26) (22) C_(1hr) (ng/mL) 1627 113.22 84.91150.98 1516 (66) (58) C_(2hr) ^(a) (ng/mL) 2248 118.49 107.61 130.481841 (30) (20) AUC_(0-t) 21944 98.78 95.91 101.75 21962 (ng · hr/mL)(27) (22) AUC_(0-inf) 23090 98.73 95.85 101.7 23104 (ng · hr/mL) (27)(21) AUC_(0-1hr) 823 105.42 68.75 161.64 814 (ng · hr/mL) (96) (82)AUC_(0-2hr) ^(b) 2761 106.73 86.55 131.62 2492 (ng · hr/mL) (52) (47)AUC_(0-4hr) ^(c) 7006 119.91 110.42 130.2 5726 (ng · hr/mL) (28) (22)T_(max) (hr) 2.328 na na na 6.971 (58) (34) T_(lag) (hr) 0.276 na na na0.219 (81) (98) T_(1/2) (hr) 5.235 na na na 6.461 (35) (66) K_(el)(1/hr) 0.145 na na na 0.137 (28) (39) *Dose Normalized to 500 mg^(a)Concentration at the median T_(max) for commercially-availableimmediate release tablet ^(b)AUC from zero the median T_(max) forcommercially-available immediate release tablet ^(c)AUC from the zero tothe median T_(max) + 2SD for commercially-available immediate releasetablet

TABLE 10 Acetaminophen Pharmacokinetics (15/500) Commer- cially-available immediate release Medium Release Formulation tablet* Mean LSM90% Cl Mean Parameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL)2720 99.19 91.61 107.39 2721 (22) (22) C_(1hr) (ng/mL) 1831 121.62 91.51161.65 1516 (54) (58) C_(2hr) ^(a) (ng/mL) 2170 116.69 105.96 128.511841 (23) (20) AUC_(0-t) 22184 100.68 97.74 103.7 21962 (ng · hr/mL)(22) (22) AUC_(0-inf) 23554 101.39 98.43 104.44 23104 (ng · hr/mL) (22)(21) AUC_(0-1hr) 974 124.39 81.52 189.79 814 (ng · hr/mL) (85) (82)AUC_(0-2hr) ^(b) 2974 117.9 95.58 145.43 2492 (ng · hr/mL) (47) (47)AUC_(0-4hr) ^(c) 7122 123.98 114.17 134.64 5726 (ng · hr/mL) (23) (22)T_(max) (hr) 2.069 na na na 6.971 (66) (34) T_(lag) (hr) 0.218 na na na0.219 (77) (98) T_(1/2) (hr) 5.696 na na na 6.461 (33) (66) K_(el)(1/hr) 0.133 na na na 0.137 (29) (39) *Dose Normalized to 500 mg^(a)Concentration at the median T_(max) for commercially-availableimmediate release tablet ^(b)AUC from zero the median T_(max) forcommercially-available immediate release tablet ^(c)AUC from the zero tothe median T_(max) + 2SD for commercially-available immediate releasetablet

TABLE 11 Acetaminophen Pharmacokinetics (15/500) Commer- cially-available immediate release Slow Release Formulation tablet* Mean LSM90% Cl Mean Parameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL)2521 93.6 86.44 101.35 2721 (18) (22) C_(1hr) (ng/mL) 1766 126.26 94.96167.87 1516 (51) (58) C_(2hr) ^(a) (ng/mL) 2113 116.18 105.48 127.961841 (18) (20) AUC_(0-t) 21947 99.61 96.7 102.61 21962 (ng · hr/mL) (25)(22) AUC_(0-inf) 23279 100.47 97.53 103.49 23104 (ng · hr/mL) (25) (21)AUC_(0-1hr) 872 115.25 75.49 175.95 814 (ng · hr/mL) (83) (82)AUC_(0-2hr) ^(b) 2811 116.49 94.42 143.73 2492 (ng · hr/mL) (43) (47)AUC_(0-4hr) ^(c) 6828 120.68 111.11 131.07 5726 (ng · hr/mL) (19) (22)T_(max) (hr) 2.184 na na na 6.971 (59) (34) T_(lag) (hr) 0.253 na na na0.219 (86) (98) T_(1/2) (hr) 5.366 na na na 6.461 (32) (66) K_(el)(1/hr) 0.141 na na na 0.137 (28) (39) *Dose Normalized to 500 mg^(a)Concentration at the median T_(max) for commercially-availableimmediate release tablet ^(b)AUC from zero the median T_(max) forcommercially-available immediate release tablet ^(c)AUC from the zero tothe median T_(max) + 2SD for commercially-available immediate releasetablet

The pharmacokinetic parameters for the medium release 15/500 formulationand the commercially-available immediate release tablet are shown inTable 12.

TABLE 12 Pharmacokinetic Profile (Mean ± SD) of Oxycodone/APAP versuscommercially- available immediate release tablet (N = 29) AUC_(0-t)AUC_(0-inf) C_(max) (ng · hr/ (ng · hr/ T_(max) K_(el) t_(1/2) Dosage(ng/mL) mL) mL) (hr) (1/hr) (hr) Oxycodone 15 mg OC/ 18.3 ± 217 ± 219 ±5.3 ± 0.156 ± 4.6 ± 500 mg 4.6 49.2 49.5 2.0 0.024 0.7 APAP Com- 22.4 ±230 ± 231 ± 8.0 ± 0.157 ± 4.5 ± mercially- 4.5* 49.8 50.0 1.7* 0.020 0.6available immediate release tablet (7.5 mg OC/325 mg APAP) Acetaminophen15 mg OC/ 2720 ± 221184 ± 23554 ± 2.1 ± 0.133 ± 5.7 ± 500 mg 608 48045234 1.4 0.039 1.9 APAP Com- 2721 ± 21962 ± 23104 ± 7.0 ± 0.137 ± 6.5 ±mercially- 584* 4772 4882 2.4* 0.054 4.3 available immediate releasetablet^(a) (7.5 mg OC/325 mg APAP) *Most values occurred after thesecond dose. ^(a)AUC and C_(max) dose-normalized to 500 mg for APAP.

The oxycodone mean plasma concentration as a function of time afteradministration of 15/500 tablets is shown in Table 13 and FIG. 5. TheAPAP mean plasma concentration over time after administration of 15/500tablets is shown in Table 14 and FIG. 6.

TABLE 13 Time Course of Oxycodone Plasma Concentration (ng/mL) Meancommer- cially available immediate Time Mean Mean Mean release (hr) FastSEM Medium SEM Slow SEM tablet SEM 0 0 0 0 0 0 0 0 0 0.17 0 0 0.13 0.110.06 0.02 0.03 0.03 0.33 0.65 0.29 1.08 0.44 0.93 0.41 1.16 0.36 0.52.09 0.55 2.98 0.95 2.55 0.96 4.03 0.9 0.67 3.74 0.91 5.29 1.25 4.15 1.17.04 0.93 1 6.89 0.98 7.36 1.11 7.6 1.24 10.23 1.11 2 12.36 0.74 12.391.04 11.24 0.73 14.94 0.81 3 14.77 0.82 14.73 0.91 13.35 0.53 14.84 0.624 16.33 0.8 16.1 0.82 15.12 0.44 12.95 0.58 5 16.28 0.67 15.89 0.8115.83 0.41 10.58 0.8 6 17.4 0.72 16.43 0.81 15.76 0.41 9.1 0.67 6.516.59 0.64 15.89 0.72 15.22 0.96 10.76 0.7 7 15.28 0.58 14.83 0.69 14.491.43 16.84 0.69 8 14.02 0.6 14.29 0.64 13.77 0.85 19.7 0.7 9 13.13 0.5713.39 0.55 13 0.78 19.08 0.65 10 11.9 0.64 12.52 0.53 11.92 0.68 16.630.57 12 8.86 0.6 9.59 0.49 10.04 0.59 10.88 0.53

TABLE 14 Time Course of Acetaminophen Plasma Concentration (ng/mL) Meancom- mercially- available immediate Time Mean Mean Mean release (hr)Fast SEM Medium SEM Slow SEM tablet SEM 0 0 0 0 0 0 0 0 0 0.17 31 18 284151 220 88 107 47 0.33 673 210 751 221 678 197 607 173 0.5 1216 266 1299275 1133 248 1181 229 0.67 1624 301 1922 301 1647 252 1653 255 1 2116258 2380 239 2296 217 1971 210 2 2922 160 2821 123 2747 93 2393 90 32736 129 2719 90 2636 94 2150 65 4 2643 120 2524 103 2424 110 1717 71 52376 112 2246 121 2130 118 1290 59 6 2263 100 2080 143 1965 107 1006 586.5 2068 93 1903 126 1774 102 1742 212 7 1830 80 1744 116 1644 98 2749232 8 1577 81 1573 103 1495 93 2790 114 9 1416 79 1407 88 1330 80 2482111 10 1286 82 1314 84 1198 71 1968 105 12 1069 89 1131 86 1089 66 118882

Example 3 Clinical Pharmacokinetic Analysis of Controlled-Release 30 mgOxycodone/500 mg Acetaminophen Bilayer Tablets—Single Dose

A single dose, four-period crossover study was conducted essentially asdescribed in Example 2, except the controlled-release bilayer tabletscontained 30 mg oxycodone and 500 mg APAP. (See selected examples fromChart No. 2.) Tables 15-17 and 18-20 present the PK data for oxycodoneand APAP, respectively. The plasma concentrations of oxycodone and APAPare presented in FIG. 7 and FIG. 8, respectively.

TABLE 15 Oxycodone Pharmacokinetics (30/500) Commer- cially- availableimmediate release Fast Release Formulation tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) (ng/mL) 39.159 82.1775.96 88.9 47.597 (28) (26) C_(1hr) (ng/mL) 20.462 77.25 54.37 109.7625.911 (74) (67) C_(2hr) ^(a) (ng/mL) 28.221 95.18 83.82 108.08 29.579(39) (32) AUC_(0-t) 393.952 92.84 89.3 96.53 425.978 (ng · hr/mL) (30)(29) AUC_(0-inf) 396.135 92.4 88.94 95.99 430.196 (ng · hr/mL) (29) (29)AUC_(0-1hr) 9.106 71.09 46.05 109.76 11.55 (ng · hr/mL) (100) (93)AUC_(0-2hr) ^(b) 33.448 82.59 67.9 100.46 39.295 (ng · hr/mL) (61) (53)AUC_(0-4hr) ^(c) 96.47 101.27 91.51 112.06 93.706 (ng · hr/mL) (38) (29)AUC_(4hr-t) ^(d) 395.522 92.4 88.95 95.99 429.507 (ng · hr/mL) (29) (29)T_(max) (hr) 4.057 na na na 6.948 (51) (33) T_(lag) (hr) 0.213 na na na0.184 (107) (66) T_(1/2) (hr) 4.398 na na na 4.32 (15) (15) K_(el)(1/hr) 0.161 na na na 0.164 (15) (16) ^(a)Concentration at the medianT_(max) for commercially-available immediate release tablet ^(b)AUC fromzero the median T_(max) for commercially-available immediate releasetablet ^(c)AUC from the zero to the median T_(max) + 2SD forcommercially-available immediate release tablet

TABLE 16 Oxycodone Pharmacokinetics (30/500) Commercially- availableimmediate Medium Release Formulation release tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) 36.731 77.14 71.2783.48 47.597 (ng/mL) (30) (26) C_(1hr) 19.758 86.12 60.48 122.62 25.911(ng/mL) (70) (67) C_(2hr) ^(a) 27.655 93.53 82.31 106.28 29.579 (ng/mL)(39) (32) AUC_(0-t) 396.026 94.17 90.55 97.92 425.978 (ng · hr/mL) (29)(29) AUC_(0-inf) 398.084 93.68 90.16 97.34 430.196 (ng · hr/mL) (29)(29) AUC_(0-1hr) 8.988 93.06 60.12 144.04 11.55 (ng · hr/mL) (85) (93)AUC_(0-2hr) ^(b) 32.695 86.02 70.64 104.74 39.295 (ng · hr/mL) (56) (53)AUC_(0-4hr) ^(c) 91.998 98.13 88.63 108.65 93.706 (ng · hr/mL) (36) (29)AUC_(4hr-t) ^(d) 397.436 93.68 90.16 97.34 429.507 (29) (29) T_(max)(hr) 4.523 na na na 6.948 (51) (33) T_(lag) (hr) 0.207 na na na 0.184(95) (66) T_(1/2) (hr) 4.369 na na na 4.32 (14) (15) K_(el) (1/hr) 0.162na na na 0.164 (14) (16) ^(a)Concentration at the median T_(max) forcommercially-available immediate release tablet ^(b)AUC from zero themedian T_(max) for commercially-available immediate release tablet^(c)AUC from the zero to the median T_(max) + 2SD forcommercially-available immediate release tablet

TABLE 17 Oxycodone Pharmacokinetics (30/500) Commercially- availableimmediate Slow Release Formulation release tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) 32.976 68.96 63.7474.6 47.597 (ng/mL) (29) (26) C_(1hr) 17.897 73.61 52.01 104.18 25.911(ng/mL) (74) (67) C_(2hr) ^(a) 23.183 78.42 69.06 89.05 29.579 (ng/mL)(33) (32) AUC_(0-t) 399.623 94.5 90.9 98.25 425.978 (ng · hr/mL) (26)(29) AUC_(0-inf) 401.362 93.88 90.36 97.52 430.196 (ng · hr/mL) (26)(29) AUC_(0-1hr) 7.643 69.93 45.52 107.44 11.55 (ng · hr/mL) (96) (93)AUC_(0-2hr) ^(b) 28.183 71.58 58.85 87.06 39.295 (ng · hr/mL) (59) (53)AUC_(0-4hr) ^(c) 82.171 86.17 77.87 95.35 93.706 (ng · hr/mL) (36) (29)AUC_(4hr-t) ^(d) 400.56 93.85 90.34 97.49 429.507 (26) (29) T_(max) (hr)3.96 na na na 6.948 (48) (33) T_(lag) (hr) 0.201 na na na 0.184 (78)(66) T_(1/2) (hr) 4.418 na na na 4.32 (17) (15) K_(el) (1/hr) 0.161 nana na 0.164 (17) (16) ^(a)Concentration at the median T_(max) forcommercially-available immediate release tablet ^(b)AUC from zero themedian T_(max) for commercially-available immediate release tablet^(c)AUC from the zero to the median T_(max) + 2SD forcommercially-available immediate release tablet

TABLE 18 Acetaminophen Pharmacokinetics (30/500) Commercially- availableimmediate Fast Release Formulation release tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) 3138 101.52 91.58122.53 3085 (ng/mL) (32) (29) C_(1hr) 2163 130.98 101.04 169.78 1777(ng/mL) (59) (59) C_(2hr) ^(a) 2386 125.37 113.22 138.82 1892 (ng/mL)(32) (28) AUC_(0-t) 21742 98.53 95.07 102.13 21897 (ng · hr/mL) (26)(23) AUC_(0-inf) 22798 99.02 95.5 102.66 22881 (ng · hr/mL) (26) (23)AUC_(0-1hr) 1260 122.71 85.05 177.03 1005 (ng · hr/mL) (85) (80)AUC_(0-2hr) ^(b) 3534 120.52 100.69 144.26 2839 (ng · hr/mL) (53) (48)AUC_(0-4hr) ^(c) 8038 130.54 119.98 142.02 6041 (ng · hr/mL) (33) (27)AUC_(4hr-t) ^(d) 14707 86.22 82.35 90.27 16720 (32) (26) T_(max) (hr)1.908 na na na 5.615 (69) (54) T_(lag) (hr) 0.236 na na na 0.178 (106)(90) T_(1/2) (hr) 4.798 na na na 5.3 (26) (43) K_(el) (1/hr) 0.153 na nana 0.152 (25) (36) *Dose Normalized to 500 mg ^(a)Concentration at themedian T_(max) for commercially-available immediate release tablet^(b)AUC from zero the median T_(max) for commercially-availableimmediate release tablet ^(c)AUC from the zero to the median T_(max) +2SD for commercially-available immediate release tablet

TABLE 19 Acetaminophen Pharmacokinetics (30/500) Commercially- availableimmediate Medium Release Formulation release tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) 2940 93.8 84.57 104.033085 (ng/mL) (38) (29) C_(1hr) 2161 139.29 107.29 180.84 1777 (ng/mL)(56) (59) C_(2hr) ^(a) 2349 125.86 113.61 139.44 1892 (ng/mL) (27) (28)AUC_(0-t) 21822 99.42 95.9 103.06 21897 (ng · hr/mL) (26) (23)AUC_(0-inf) 23107 100.76 97.16 104.49 22881 (ng · hr/mL) (26) (23)AUC_(0-1hr) 1342 155.89 107.81 225.4 1005 (ng · hr/mL) (81) (80)AUC_(0-2hr) ^(b) 3596 129.14 107.79 154.73 2839 (ng · hr/mL) (52) (48)AUC_(0-4hr) ^(c) 7880 130.08 119.51 141.59 6041 (ng · hr/mL) (32) (27)AUC_(4hr-t) ^(d) 15040 88.93 84.92 93.13 16720 (29) (26) T_(max) (hr)1.724 na na na 5.615 (62) (54) T_(lag) (hr) 0.19 na na na 0.178 (114)(90) T_(1/2) (hr) 6.116 na na na 5.3 (63) (43) K_(el) (1/hr) .0139 na nana 0.152 (37) (36) *Dose Normalized to 500 mg ^(a)Concentration at themedian T_(max) for commercially-available immediate release tablet^(b)AUC from zero the median T_(max) for commercially-availableimmediate release tablet ^(c)AUC from the zero to the median T_(max) +2SD for commercially-available immediate release tablet

TABLE 20 Acetaminophen Pharmacokinetics (30/500) Commercially- availableimmediate Slow Release Formulation release tablet Mean LSM 90% Cl MeanParameter (% CV) Ratio Lower Upper (% CV) C_(max) 2734 88.33 79.68 97.913085 (ng/mL) (33) (29) C_(1hr) 1989 120.26 93.05 155.44 1777 (ng/mL)(53) (59) C_(2hr) ^(a) 2131 112.77 101.84 124.86 1892 (ng/mL) (25) (28)AUC_(0-t) 21272 97.1 93.68 100.64 21897 (ng · hr/mL) (23) (23)AUC_(0-inf) 22504 98.45 94.95 102.07 22881 (ng · hr/mL) (22) (23)AUC_(0-1hr) 1092 120.91 84.15 173.72 1005 (ng · hr/mL) (76) (80)AUC_(0-2hr) ^(b) 3152 112.74 94.19 134.94 2839 (ng · hr/mL) (45) (48)AUC_(0-4hr) ^(c) 7217 119.31 109.5 129.61 6041 (ng · hr/mL) (26) (27)AUC_(4hr-t) ^(d) 15227 90.59 86.52 94.85 16720 (26) (26) T_(max) (hr)1.897 na na na 5.615 (56) (54) T_(lag) (hr) 0.196 na na na 0.178 (79)(90) T_(1/2) (hr) 4.843 na na na 5.3 (27) (43) K_(el) (1/hr) 0.152 na nana 0.152 (24) (36) *Dose Normalized to 500 mg ^(a)Concentration at themedian T_(max) for commercially-available immediate release tablet^(b)AUC from zero the median T_(max) for commercially-availableimmediate release tablet ^(c)AUC from the zero to the median T_(max) +2SD for commercially-available immediate release tablet

The pharmacokinetic parameters for the medium release 30/500 formulationand the commercially-available immediate release tablet are shown inTable 21.

TABLE 21 Pharmacokinetic Profile (Mean ± SD) of Oxycodone/APAP versusCommercially-available immediate release tablet (N = 29) AUC_(0-t)AUC_(0-inf) C_(max) (ng · hr/ (ng · hr/ T_(max) K_(el) t_(1/2) Dosage(ng/mL) mL) mL) (hr) (1/hr) (hr) Oxycodone 30 mg 36.7 ± 396 ± 398 ± 4.5± 0.162 ± 4.4 ± OC/500 mg 10.9 116 115 2.3 0.023 0.6 APAP Com- 47.6 ±426 ± 430 ± 6.9 ± 0.164 ± 4.3 ± mercially- 12.3* 125 124 2.3* 0.026 0.6available immediate release tablet^(a) (7.5 mg OC/325 mg APAP)Acetaminophen 30 mg 2940 ± 21822 ± 23107 ± 1.7 ± 0.139 ± 6.1 ± OC/500 mg1105 5630 5927 1.1 0.052 3.9 APAP Com- 3085 ± 21897 ± 22881 ± 5.6± 0.152± 5.3 ± mercially- 899* 5125 5362 3.0* 0.055 2.3 available immediaterelease tablet^(a) (7.5 mg OC/325 mg APAP) *Most values occurred afterthe second dose. ^(a)AUC and Cmax dose-normalized to 30 mg for OC and500 mg for APAP.

Example 4 Clinical Pharmacokinetic Analysis of Controlled-Release 15 mgOxycodone/650 mg Acetaminophen Bilayer Tablets—Single Dose

The following study evaluated the bioavailability, pharmacokinetics,dose-proportionality, and safety of 1 or 2 tablets of 15 mg of acomposition comprising OC/650 mg APAP (1 dose) (see selected examplefrom Chart No. 1) compared to 1 tablet of the commercially-availableimmediate release tablet under fed conditions. The ER layer contained75% of the total amount of the oxycodone in the tablet, 50% of the totalamount of APAP in the tablet, and 45% (w/w) POLYOX® 1105. The IR layercontained 25% of the total amount of oxycodone in the tablet and 50% ofthe total amount of APAP. This study was conducted in 42 male and femalehealthy subjects.

PK parameters for oxycodone are presented in Table 22. Plasmaconcentrations of OC for the 1 tablet dosing configuration of 15/650showed a median t_(lag) of 0.25 hours, while there was no lag time forplasma concentrations of OC for the 2 tablet dosing configuration of15/650 and the commercially-available immediate release tablet under fedconditions. As illustrated in FIG. 9 demonstrating the plasmaconcentrations of oxycodone versus time of treatment (i.e., Treatment Awas one tablet of 15 mg oxycodone/650 mg acetaminophen administeredorally under fed conditions; Treatment B was two tablets of 15 mgoxycodone/650 mg acetaminophen administered orally one at a time underfed conditions; and Treatment C was one tablet of thecommercially-available immediate release tablet (7.5 mg oxycodone/325 mgacetaminophen) administered orally every 6 hours for 2 doses under fedconditions). Plasma concentrations of OC rose rapidly afteradministration of 15/650 formulation in a similar fashion tocommercially-available immediate release tablet. Peak plasma levels ofOC for the 15/650 tablets, however, were biphasic. Peak levels wereobserved at about 2-3 hours and about 6 hours for the 1 or 2 tabletdosing configuration of the 15/650 formulation. In contrast, the peakplasma level of OC for the commercially-available immediate releasetablet was about 7-8 hours after the initial dose of thecommercially-available immediate release tablet (˜1-2 hr after thesecond dose). Mean plasma concentrations of OC from 15/650 formulationswere detectable through 48 hours following all treatments and t_(1/2)was about 4 hours across all treatments.

TABLE 22 Pharmacokinetic Parameter Estimates (Mean ± SD) of OxycodoneFollowing Administration of 15 mg Oxycodone/650 mg APAP versusCommercially-available immediate release tablet C_(max) AUC_(0−t)AUC_(0−inf) T_(max) ^(a) T_(lag) ^(a) t_(1/2) Dosage (ng/mL) (ng ·hr/mL) (ng · hr/mL) (hr) (hr) (hr) One tablet 17.68 199.60 201.6 3.000.25 4.18 (N = 25) (4.42) (59.52) (59.27) (1.00-12.45) (0.00-0.75)(0.77) Treatment A Two tablets 29.18 414.73 417.41^(b) 5.00 0.00 4.11b(N = 25) (6.53) (109.87) (112.17) (1.00-12.00) (0.00-0.50) (0.67)Treatment B Commercially- 20.34 199.63 201.76 7.00 0.00 4.08 available(4.81) (60.53) (60.24) (0.50-9.00) (0.00-1.00) (0.64) immediate releasetablet (7.5 mg OC/325 mg APAP (N = 25) Treatment C ^(a)T_(max) andt_(lag) median (minimum-maximum) ^(b)N = 24

PK parameters for APAP are presented in Table 23. Plasma concentrationsof APAP for the 1 tablet dosing configuration of 15/650 showed a mediant_(lag) of 0.25 hour, while there was no lag in the appearance of APAPin plasma for the 2 tablet dosing configuration of 15/650 and thecommercially-available immediate release tablet. Plasma concentrationsof APAP rose rapidly after administration of the 15/650 formulations,similar to that observed with RDL. (See FIG. 10). Peak plasma levels ofAPAP following administration of the 1 tablet and 2 tablet dosingconfigurations of 15/650 were observed at approximately 2 hours (with ashoulder peak at 5-6 hours) after dosing compared with 1 hour after thesecond dose of the commercially-available immediate release tablet. Meanplasma concentrations of APAP were detectable through 36 hours followingall treatments and the mean t_(1/2) was approximately 6 to 8 hoursacross treatment groups.

TABLE 23 Pharmacokinetic Parameter Estimates (Mean ± SD) of APAPFollowing Administration of 15 mg Oxycodone/650 mg APAP versusCommercially-available immediate release tablet C_(max) AUC_(0−t)AUC_(0−inf) T_(max) ^(a) T_(lag) ^(a) t_(1/2) Dosage (ng/mL) (ng ·hr/mL) (ng · hr/mL) (hr) (hr) (hr) One tablet 3822 30239 32194^(c) 2.000.25 6.17^(c) (N = 25) (874) (5673) (6437) (0.50-4.00) (0.00-1.00)(2.22) Two tablets 6941 64783 67600^(d) 2.00 0.00 7.67^(d) (N = 25)(1989) (15017) (14655) (0.50-5.00) (0.00-0.50) (4.06) Commercially- 362930137 30802^(c) 6.50 0.00 5.89^(c) available (841) (6426) (6697)(0.50-9.00) (0.00-1.00) (2.63) immediate release tablet (7.5 mg OC/325mg APAP (N = 25) ^(a)T_(max) and t_(lag) median (minimum-maximum) ^(c)N= 21 ^(d)N = 23

Example 5 Clinical Pharmacokinetic Analysis of Controlled-Release 15 mgOxycodone/650 mg Acetaminophen Bilayer Tablets—Multiple Doses

The following study evaluated the steady state bioavailability,pharmacokinetics, and safety of a 15 mg OC/650 mg APAP compositionadministered (see selected example from Chart No. 2) orally as 1 tablet(Treatment A) or 2 tablets (Treatment B) every 12 hours (9 doses)compared to 2 tablets of the commercially-available immediate releasetablet (2×7.5 mg OC/325 mg APAP) (Treatment C) dosed every 6 hours for4.5 days (18 doses) under fed conditions with 48 male and femalesubjects in equal distribution.

The pharmacokinetic (PK) parameters of OC are presented in Table 24. ThePK behavior of OC on Study Day 1 was similar to that observed in thesingle dose study (see Table 22). There was a slight lag (median tlag0.25 hr) in the appearance of OC following the 1 tablet dose of 15 mgOC/650 mg APAP. No lag was observed following dosing with 2 tablets of15 mg OC/650 mg APAP or the commercially-available immediate releasetablet. Peak plasma levels were observed at 4 and 6 hours afteradministration of 1 and 2 tablets of the 15/650 formulation,respectively, and at 1.5 hours after the second dose of thecommercially-available immediate release tablet. (See FIG. 11). Minimum(trough) plasma concentrations (C_(min)) of OC achieved steady-statelevels by Day 2 for 15/650 formulations and by Day 3 for thecommercially-available immediate release tablet.

TABLE 24 Oxycodone Pharmacokinetic Parameters C_(max) AUC_(0-t) T_(max)^(a) T_(lag) ^(a) t_(1/2) Dosage (ng/mL) (ng · hr/mL) (hr) (hr) (hr) A:One tablet 18.79 149.68^(c) 4.00 0.25 Day 1 Day 1 (5.00) (37.92) (2.00-(0.00- (N = 20) 8.00) 0.50) B: Two tablets 33.57 280.45^(c) 5.93 0.00Day 1 Day 1 (8.41) (62.61) (1.00- (0.00- (N = 20) 11.92) 0.25) C:Commercially- 36.02 278.60^(c) 7.50 0.00 Day 1 available immediate(10.52) (67.17) (0.75- (0.00- release tablet 11.92) 0.33) (7.5 mg OC/325mg APAP Day 1 (N = 20) A: One tablet 27.26 223.10^(c) 3.00 Day 56.06^(d) Day 5 (6.33) (59.45) (1.00- (1.91) (N = 20) 5.92) B: Twotablets 50.70 433.37^(c) 3.00 Day 5 6.35 Day 5 (10.95) (93.21) (2.00-(1.89) (N = 20) 7.00) C: Commercially- 52.41 435.70^(c) 2.00 Day 55.93^(d) available immediate (12.40) (98.68) (0.50- (1.68) releasetablet 8.02) (7.5 mg OC/325 mg APAP Day 5 (N = 20) ^(a)T_(max) andt_(lag) median (minimum-maximum) ^(c)Day 1 - AUC_(0-12h); Day 5 -AUC_(0-12h) ^(ss) ^(d)N = 19

On Day 5 of the study, the maximum plasma OC concentration atsteady-state (C_(max) ^(ss)) was 27.3 ng/mL following 4.5 days of dosingwith 1 tablet of 15 mg OC/650 mg APAP administered every 12 hours.C_(max) ^(ss) following 2 tablets of 15 mg OC/650 mg APAP administeredevery 12 hours or the commercially-available immediate release tabletadministered Q6 hours for 4.5 days were 50.7 ng/mL and 52.4 ng/mL,respectively. Median T_(max) ^(ss) was observed at 3 hours following 1tablet or 2 tablets of 15/650 and at 2 hours following the first dailydose of the commercially-available immediate release tablet.

PK parameters for APAP are presented in Table 25. Acetaminophen wasrapidly absorbed following a single dose of 1 or 2 tablets of 15/650 andin a similar fashion to the commercially-available immediate releasetablet (see FIG. 12). There was no lag in plasma concentrationsfollowing any of the three dosing regimens. Peak APAP plasmaconcentrations were observed at 1 hour after administration of 1 or 2tablets of 15/650 and at 0.9 hours after the first dose of thecommercially-available immediate release tablet on Day 1. After a singleadministration of 15/650, C_(max) for APAP was proportional with respectto the amount of APAP in 1 or 2 tablets of 15/650 (i.e., 1 tablet—3942ng/mL; 2 tablets—7536 ng/mL). Minimum (trough) concentrations (C_(min))of APAP achieved steady-state levels by Day 2 for 1 tablet of 15/650, byDay 4 for 2 tablets of 15/650 and by the second dose on Day 1 for thecommercially-available immediate release tablet.

TABLE 25 Acetaminophen Pharmacokinetic Parameters C_(max) AUC_(0-t)T_(max) ^(a) T_(lag) ^(a) t_(1/2) Dosage (ng/mL) (ng · hr/mL) (hr) (hr)(hr) A: One tablet 3942 22928^(g) 1.00 0.00 Day 1 Day 1 (1168) (7331)(0.50- (0.00- (N = 20) 5.93) 0.28) B: Two tablets 7536 44254^(g) 1.000.00 Day 1 Day 1 (2205) (13885) (0.28- (0.00- (N = 20) 4.00) 0.25) C:Commercially- 6757 43634^(g) 0.90 0.00 Day 1 available immediate (1949)(12357) (0.32- (0.00- release tablet 11.92 0.25) (7.5 mg OC/325 mg APAPDay 1 (N = 20) A: One tablet 4635 26968^(g) 1.00 Day 5 7.06 Day 5 (1330)(9134) (0.50- (2.24) (N = 20) 3.00) B: Two tablets 8206 50221^(g) 1.00Day 5 7.46 Day 5 (2666) (18415) (0.30- (1.85) (N = 20) 4.00) C:Commercially- 7433 50678^(g) 1.50 Day 5 6.79^(h) available immediate(1979) (15565) (0.25- (2.47) release tablet 8.02) (7.5 mg OC/325 mg APAPDay 5 (N = 20) ^(a)T_(max) and t_(lag) median (minimum-maximum) ^(g)Day1 - AUC_(0-12h); Day 5 - AUC_(0-12h) ^(ss) ^(hr)N = 17

On Day 5 of the study, median T_(max) ^(ss) for APAP was observed at 1hour following 1 or 2 tablets of 15/650 and at 1.5 hours following thefirst daily dose of the commercially-available immediate release tableton Day 5. Maximum plasma APAP concentration at steady-state (C_(max)^(ss)) was 4635 ng/mL following 4.5 days of dosing with 1 tablet of15/650 every 12 hours (Table 25). C_(max) ^(ss) following 2 tablets of15/650 administered every 12 hours and for the commercially-availableimmediate release tablet administered Q6 hours for 4.5 days were 8206and 7433 ng/mL, respectively.

Example 6 Clinical Pharmacokinetic Analysis of Controlled-Release 15 mgOxycodone/650 mg Acetaminophen Bilayer Tablets Under Fed and FastedConditions

Two open-label, randomized, two-period crossover studies were conductedto evaluate the effect of food on the pharmacokinetics, bioavailabilityand safety of the 15 mg oxycodone/650 mg APAP composition (see selectedexample from Chart No. 2) using a 1 tablet or 2 tablet dosingconfiguration in normal, healthy subjects. Studies were conducted in 48subjects under fed (FDA high fat breakfast) or fasted conditions.

Tables 26 and 27 present the pharmacokinetic data for oxycodone (OC) andAPAP, respectively. FIGS. 13 and 14 present the plasma concentration ofOC following administration of one tablet and two tablets, respectively,under fed (Treatment A) or fasted (Treatment B) conditions. FIGS. 15 and16 present the plasma concentration of APAP following administration ofone tablet and two tablets, respectively, under fed (Treatment A) orfasted (Treatment B) conditions.

TABLE 26 Oxycodone Pharmacokinetics (15/650) State C_(max) AUC_(0−t)AUC_(0−inf) T_(max) ^(a) t_(lag) ^(a) t_(1/2) Dose (N) (ng/mL) (ng ·hr/mL) (ng · hr/mL) (hr) (hr) (hr) One fed 19.03 219.23 221.06 5.00 0.253.94 tablet (28) (4.20) (55.99) (55.88) (1.00-12.00) (0.00-0.50) (0.69)Two fed 30.58 414.01 415.88 5.00 0.25 4.42 tablets (17) (6.57) (104.76)(104.86) (0.75-12.00) (0.00-0.27) (0.97) One fasted 18.31 196.51 198.333.50 0.00 4.25 tablet (28) (4.67) (53.04) (52.82) (0.50-10.00)(0.00-0.25) (0.59) Two fasted 33.69 390.33 392.15 5.00 0.00 4.80 tablets(17) (7.45) (145.27) (145.81) (2.00-5.20) (0.00-0.25) (1.07) ^(a)T_(max)and t_(lag) median (minimum-maximum)

Plasma concentrations (Table 26; FIGS. 13 and 14) of OC rose rapidlywith the median T_(max) observed at about 4 to 5 hr under both fed andfasted conditions for both the 1- and 2-tablet dose configurations. OCplasma levels were biphasic—with a first peak at about 3 hours and asecond peak at about 5 hours. The C_(max) values (at 5 hours) for OCunder fed (1 and 2 tablets, 19.0 and 30.6 ng/mL) conditions wereequivalent to those observed under fasted (1 and 2 tablets, 18.3 and33.7 ng/mL) conditions for both the 1 tablet and 2 tablet dosingconfigurations.

TABLE 27 Acetaminophen Pharmacokinetics (15/650) State C_(max) AUC_(0−t)AUC_(0−inf) T_(max) ^(a) t_(lag) ^(a) t_(1/2) Dose (N) (ng/mL) (ng ·hr/mL) (ng · hr/mL) (hr) (hr) (hr) One tablet fed 4374 31480 32552 1.000.00 4.65 (28) (1286) (9316) (9489) (0.50, 5.00) (0.00-0.50) (1.26) Twotablets fed 6341 62904 68839^(b) 2.00 0.00 7.02^(b) (17) (1698) (19294)(19826) (0.75-6.00) (0.00-0.25) (1.77) One tablet fasted 5511 3187633860 0.75 0.00 5.19^(e) (28) (2095) (103339) (10731) (0.25, 5.00)(0.00-0.25) (1.50) Two tablets fasted 10428 61164 65281 0.75 0.00 5.6(17) (3529) (16552) (15711) (0.25-5.00) (0.00-0.00) (1.49) ^(a)T_(max)and t_(lag) median (minimum-maximum) ^(b)N = 12 ^(e)N = 27 ^(f)N = 13

Plasma concentrations (Table 27; FIGS. 15 and 16) of APAP rose rapidlyfollowing 1 tablet dosed under fed and fasted conditions with similarT_(max) values (1.0 hour and 0.8 hour). T_(max) was observed soonerfollowing 2 tablets given under fasted conditions (0.8 hour) than underfed conditions (2 hours). Plasma concentrations of APAP were lower underfed conditions than under fasted conditions with fed C_(max) values of4374 ng/mL (1 tablet) and 6341 ng/mL (2 tablets) and fasted C_(max)values of 5511 ng/mL (1 tablet) and 10,428 ng/mL (2 tablets).Nevertheless, the peak concentrations demonstrate that there was only aslight, minimal food effect on the absorption of APAP, which isconsistent with that observed for other oxycodone and acetaminophenproducts. Thus, there is no meaningful food effect seen with thiscomposition, and as such, the composition can to be administered withoutregard to food.

Example 7 Abuse Potential of Controlled-Release Formulations

It has long been theorized that the desirability of a drug of abuse isrelated to the speed with which it reaches maximum concentration in theplasma of the user. Basic science and clinical observation suggest thata shortened time to maximum plasma concentration (t_(max)) and aheightened maximum plasma concentration (C_(max)) would increase theeuphoric effects conferred by a drug. The abuse quotient (AQ) is arelatively new concept that attempts to predict the abuse potential ofdrugs. The AQ refers to the two PK parameters expressed as a ratio:AQ=C_(max)/t_(max). The abuse potential of a drug increases as the valueof the AQ increases, either by heightening C_(max) or shorteningt_(max).

Table 28 presents the AQs for various extended release formulationsdisclosed herein (see, e.g., selected examples from Chart Nos. 1 and 2)and several commercially available formulations.

TABLE 28 Abuse Quotient Formulation C_(max) (ng/mL) t_(max) (hr) AQ15/500 - Fast 18.8 4.95 3.80 15/500 - Medium 18.27 5.31 3.44 15/500 -Slow 17.4 5.66 3.07 15/650 - 1 tablet 17.68 3.90 4.53 15/650 - 2 tablets14.59* 5.03 2.90 7.5/325 - 1 tablet 16.82 3.71 4.53 7.5/325 - 2 tablets16.39 3.17 5.17 Percocet 22.43 2.16 10.38 Oxycontin 17.35 3.54 4.90OxyER 19.61 4.11 4.77 *dose normalized to 15 mg

Example 8 Ethanol Release Testing at a 150 rpm Paddle Speed

To asses the potential for dose dumping, the in vitro dissolution ofoxycodone and APAP from 7.5 mg OC/325 mg APAP tablets was tested in 0.1N HCl containing 0%, 5%, 20%, or 40% v/v ethanol. The ER layer of the7.5/325 tablets contained 5.625 mg of OC, 162.5 mg of APAP, and 45%(w/w) POLYOX® 1105, and the IR layer contained 1.875 mg of OC and 162.5mg of APAP. (See selected example from Chart No. 1.) For each profile,twelve tablets were weighed, placed in a sinker, and dropped into anequilibrated USP Type II apparatus (paddles) that contained 900 mL of(helium sparged) 0.1 N HCl (containing either 0%, 5%, 20%, or 40%ethanol) heated to 37° C. The mixture was stirred at ˜150 rpm and thetemperature was maintained at 37° C. for 120 minutes. The bath vesselwas covered with a low evaporation vessel cover. Samples were removed at15, 30, 45, 60, 75, 90, 105, and 120 minutes. Each sample was filteredthrough a 0.45 μm filter and analyzed by HPLC using standard procedures.

Tables 29, 30, 31, and 32 present the percent release of OC and APAP inthe presence of 0%, 5%, 20%, and 40% ethanol, respectively. FIG. 17presents dissolution profiles for OC and FIG. 18 presents dissolutionprofiles for APAP in the presence of 0%, 5%, 20%, and 40% ethanol. Thesedata reveal that for both OC and APAP, the dissolution in 5%, 20%, or40% ethanol was either comparable or slower than the dissolution in 0%ethanol, indicating no dose dumping for this formulation.

TABLE 29 Percent Release in 0% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 32.0 2.7 31.1 33.4 52.92.7 50.6 56.0 30 37.6 2.4 36.5 39.2 55.6 2.5 53.5 58.6 45 42.3 2.6 40.944.4 58.1 2.5 56.0 61.1 60 46.5 2.5 45.0 48.7 60.5 2.4 58.4 63.5 75 50.42.5 48.7 52.5 62.9 2.4 60.8 65.9 90 54.1 2.4 52.1 56.2 65.0 2.3 62.968.0 105 57.7 2.1 55.6 59.8 67.1 2.3 65.0 70.1 120 61.1 2.2 58.9 63.569.1 2.2 66.9 72.1

TABLE 30 Percent Release in 5% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 31.2 2.4 30.2 32.4 52.11.5 50.5 53.5 30 36.9 3.2 35.1 39.0 54.9 1.6 53.4 56.4 45 41.5 3.3 39.144.0 57.2 1.5 55.7 58.7 60 45.5 3.5 43.4 48.2 59.4 1.5 57.9 60.9 75 49.42.6 47.9 52.5 61.5 1.5 60.0 63.0 90 52.9 3.5 50.7 56.1 63.4 1.5 61.965.0 105 56.2 1.8 54.0 57.8 65.4 1.5 63.8 66.9 120 59.3 2.8 56.7 61.767.2 1.5 65.6 68.7

TABLE 31 Percent Release in 20% Ethanol Time OC APAP (Min) Mean RSDMinimum Maximum Mean RSD Minimum Maximum 15 28.5 4.1 26.5 30.3 51.3 2.948.2 53.1 30 33.6 3.3 32.3 35.7 54.1 2.3 51.3 55.7 45 38.3 2.8 35.7 39.956.3 2.2 53.7 58.0 60 41.8 3.6 38.1 44.1 58.3 2.1 55.6 59.9 75 45.6 3.043.4 48.8 60.2 2.0 57.7 61.8 90 48.7 3.3 46.1 52.0 62.0 2.0 59.4 63.6105 51.4 3.0 49.1 53.7 63.7 1.9 61.1 65.2 120 54.3 2.7 51.3 56.7 65.41.9 62.9 66.8

TABLE 32 Percent Release in 40% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 10.3 16.3 7.8 13.7 20.716.3 15.8 25.9 30 20.7 8.6 16.5 23.0 37.1 7.7 31.4 41.4 45 28.6 10.424.4 33.4 44.4 2.6 42.2 45.8 60 31.3 5.9 29.2 35.0 47.0 1.4 45.9 48.0 7534.5 6.5 30.3 38.1 49.0 1.4 47.7 49.8 90 36.8 7.0 33.9 41.2 50.5 1.549.2 51.6 105 38.5 6.8 35.3 44.0 51.9 1.7 50.4 53.1 120 40.7 4.5 38.043.5 53.2 1.4 51.5 54.1

Example 9 Clinical Pharmacokinetic Analysis of an Extended ReleaseFormulation of Oxycodone/Acetaminophen Administered Under Fed and FastedConditions

An open-label, randomized, three-period crossover study was conducted toevaluate the pharmacokinetics (PK), bioavailability, and safety of twotablets of a multi-layer extended-release formulation (each tabletcomprising 7.5 mg oxycodone hydrochloride/325 mg acetaminophen),administered as a single dose in normal, healthy subjects under fed(high-fat or low-fat meal) and fasted conditions (i.e., 10 hr fast).

This single center, open-label, randomized, 3-period, 6-sequencecrossover study in normal, healthy subjects was designed to evaluate theeffect of a high-fat and low-fat meal on the PK, bioavailability, andsafety of a multilayer ER tablet formulation of 7.5 mg OC/325 mg APAP(see selected example from Chart No. 1). The formulation was orallyadministered as 2 tablets (15 mg OC/650 mg APAP total dose) under 2types of fed (high-fat and low-fat) and fasted conditions. Forty-eightsubjects were enrolled and 31 subjects completed the study. Onlysubjects that completed all 3 study periods have been included in the PKevaluation.

Following a 10 hour overnight fast, subjects randomized to Treatment Aconsumed an entire standardized FDA high-fat breakfast (approximately1,000±100 calories and approximately 50% from fat); those receivingTreatment B consumed an entire low-fat breakfast (approximately 800±80calories and approximately 25% to 30% from fat). Breakfasts wereconsumed within 30 minutes prior to Hour 0 study drug administration.Subjects who could not consume the entire breakfast in the allotted timewere dropped from the study. Subjects randomized to Treatment C wereadministered study drug under fasted conditions following an overnightfast of at least 10 hours. No food was allowed for the first 4 hourspostdose. Blood samples were collected pre-dose (up to 60 minutes priorto dose), and at 15 min, 30 min, 45 min and 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 16, 18, 20, 24, 36 and 48 hours post-dose, and the resultingplasma samples were analyzed for OC and APAP using a validated liquidchromatography-tandem mass spectrometry assay with a linear range of0.100 to 100 ng/mL for OC and 100 to 50,000 ng/mL for APAP.Pharmacokinetic parameters, as detailed above in Example 2, weredetermined.

Tables 33 and 34 presents PK parameters for OC under the three treatmentconditions, and FIG. 19 presents plasma OC concentration-time profilesfor the treatments. Mean plasma concentration profiles of OC revealedthat OC was rapidly absorbed under both fed (high and low fat meal) andfasted conditions. There was a slight lag (median 0.25 hours) when theformulation was administered after a meal (high and low fat). The medianof the time of observed maximum plasma concentrations (T_(max)) were 4hours and 3 hours after administration under low fat and fastedconditions, respectively. Median T_(max) for OC under high fatconditions was significantly delayed, as compared to fasted conditions(5 hr vs. 3 hr; P<0.05). Average maximum plasma OC concentrations(C_(max)) were 19.94 ng/mL after a low fat breakfast, 17.90 ng/mL aftera high fat breakfast, and 15.91 ng/mL under fasted conditions.

TABLE 33 Oxycodone Pharmacokinetic Estimates (2 tablets of 7.5/325)Treatment A Treatment B Treatment C High Fat Low Fat Fasted Mean (SD)Mean (SD) Mean (SD) Parameter (N = 31) (N = 31) (N = 31) AUC_(0-t) (ng ·hr/mL) 219.41 (54.07) 219.49 (57.29) 190.70 (50.03) AUC_(0-inf) (ng ·hr/mL) 221.00 (54.14) 221.38 (56.95) 192.63 (49.69) C_(max) (ng/mL)17.90 (4.25) 19.94 (4.66) 15.91 (3.43) T_(max) (h)^(a) 5.00 (1.00-12.00)4.00 (1.00-5.00) 3.00 (0.75-8.00) K_(el) (1/h) 0.1682 (0.0298) 0.1693(0.0321) 0.1502 (0.0269) t_(lag) (h)^(a) 0.25 (0.00-1.00) 0.25(0.00-0.75) 0.00 (0.00-0.25) t_(1/2) (h) 4.26 (0.83) 4.26 (0.91) 4.76(0.87) ^(a)Median (minimum-maximum).

A comparison of C_(max) showed that OC concentrations were 12% and 25%higher when the formulation was given under high fat (Treatment A) andlow fat (Treatment B) conditions, compared to fasted conditions(Treatment C; see Table 33). The C_(max) for Treatment A wasbioequivalent to both Treatments B (84%-96%) and C (105%-120%) as the90% CIs for the geometric ratios were contained within 80% to 125% (seeTable 34). The C_(max) observed for Treatment B was not bioequivalent toTreatment C (117%-134%). AUCs were approximately 15% higher when theformulation was administered under fed conditions (high and low fat), ascompared to fasted conditions (Table 33). AUC for both Treatments A andB (high fat and low fat) were bioequivalent to Treatment C (fasted;111%-121% and 111%-120% for AUC0-t and 111%-120% and 110%-120% forAUC0-inf) (Table 34). The apparent plasma terminal elimination half-life(t1/2) for OC was similar when the formulation was administered underfed (4 hours) and fasted conditions (5 hours).

TABLE 34 Oxycodone Geometric LSMEANS Ratio (%) (90% Cl) Treatment A/CTreatment B/C Treatment A/B Fed (High Fed (Low Fed (High Fat)/ ParameterFat)/Fasted Fat)/Fasted Fed (Low Fat) AUC_(0-inf) 115.41 115.09 100.28(ng · hr/mL)^(a) (110.63, 120.41) (110.38, 120.01) (96.18, 104.55)115.85 115.30 100.47 AUC_(0-t) (ng · hr/mL)^(a) (111.00, 120.90)(110.54, 120.27) (96.34, 104.79) 112.11 125.16 89.57 C_(max) (ng/mL)^(a)(104.61, 120.16) (116.88, 134.03) (83.67, 95.90) ^(a)N = 31.

PK parameters for APAP are presented in Tables 35 and 36 and the plasmaAPAP concentration-time profiles are presented in FIG. 20. APAP wasrapidly absorbed following administration under fed (high and low fatmeals) and fasted conditions. There was a slight lag when theformulation was administered after a low fat breakfast (median lag time[t_(lag)] 0.25 hours). There was no lag in the absorption of APAP whenadministered following a high fast breakfast or after fasting. The timeto C_(max) was significantly (P<0.05) longer when administered after ameal (high and low fat; median T_(max)=2 hours) than when administeredunder fasted conditions (median T_(max)=0.5 hour). Average C_(max)values for APAP were lower after a high (3,775 ng/mL) and low fat (3,863ng/mL) meal than when administered under fasted conditions (5,175ng/mL). Geometric mean ratios for C_(max) following Treatments A and Bwere 24% to 23% lower than for Treatment C (Table 36). The 90% CIs forC_(max) following Treatment A (70%-82%) and Treatment B (72%-83%) withreference to fasted state were outside the bioequivalent range of80%-125%. The AUCs for APAP were almost identical when the formulationwas administered under high fat, low fat, or fasting conditions.(Comparison of geometric mean ratios of AUC_(0-t) and AUC_(0 inf) forTreatments A (90% CI 97%-103% and 96%-102%) and B (90% CI 96%-101% and94% to 100%) with those for Treatment C showed that treatments werebioequivalent. The t_(1/2) for APAP after the formulation wasadministered after a high or low fat meal (5 hours) was slightly shorterthan when administered under fasted conditions (7 hours).

TABLE 35 APAP Pharmacokinetic Estimates (2 tablets of 7.5/325) TreatmentA Treatment B Treatment C Fed (High Fat) Fed (Low Fat) Fasted Mean (SD)Mean (SD) Mean (SD) Parameter (N = 31) (N = 31) (N = 31) AUC_(0-t)29617.96 29346.82 29763.19 (ng · hr/mL) (7765.99) (7869.75) (7592.89)AUC_(0-inf) 31457.06 30550.48 (8051.47) 31807.70 (ng · hr/mL)(7973.16)^(a) (7923.30)^(a) C_(max) (ng/mL) 3774.52 (949.84) 3862.90(978.08) 5175.48 (1731.31) T_(max) (h)^(b) 2.00 2.00 0.53 (0.50-5.00)(0.50-5.00) (0.23-5.00) K_(el) (1/h) 0.1564 (0.0363)^(a) 0.1593 (0.0408)0.1146 (0.0360)^(a) t_(lag) (h)^(b) 0.00 0.25 0.00 (0.00-1.00)(0.00-0.50) (0.00-0.25) t_(1/2) (h) 4.66 (1.08)^(a) 4.71 (1.60) 6.63(1.99)^(a) ^(a)N = 29 ^(b)Median (minimum-maximum).

TABLE 36 APAP Geometric LSMEANS Ratio (%) (90% Cl) Treatment A/CTreatment B/C Treatment A/B Fed (High Fed (Low Fed (High Fat)/ ParameterFat)/Fasted Fat)/Fasted Fed (Low Fat) AUC_(0-inf) 98.60 96.56 102.12 (ng· hr/mL)^(a) (95.75, 101.54) (93.80, 99.39) (99.20, 105.11) AUC_(0-t)99.88 98.79 101.10 (ng · hr/mL)^(b) (97.31, 102.52) (96.27, 101.37)(98.54, 103.74) C_(max) (ng/mL)^(b) 76.00 77.18 98.48 (70.49, 81.94)(71.65, 83.13) (91.45, 106.05) ^(a)N = 27 ^(b)N = 31.

In summary, total exposure (AUC) for OC was slightly increased (by about15%) when the formulation was administered with food (after high- orlow-fat meal); however, AUCs for OC were equivalent between alltreatments (high fat vs. fasted, low fat vs. fasted and high fat vs. lowfat). Peak exposure (C_(max)) for OC was 12% and 25% higher under highfat and low-fat conditions, respectively, compared to fasted conditions.The C_(max) for OC after a high-fat meal was bioequivalent to fastedconditions, as well as to low fat conditions, whereas the C_(max) underlow fat conditions was not equivalent to those under fasted conditions.The AUCs for APAP were equivalent between all treatments (high fat vs.fasted, low fat vs. fasted, and high fat vs. low fat). The peak exposure(C_(max)) for APAP was decreased by about 24% in fed (high- and low-fat)states as compared to the fasted state.

Example 10 Clinical Pharmacokinetic Analysis of an Extended ReleaseFormulation of 7.5 mg Oxycodone/325 mg Acetaminophen—Single Dose

An open-label, randomized, 3-period crossover study was performed toevaluate the single dose pharmacokinetic (PK) parameters,bioavailability, and safety of an extended-release formulationcontaining 7.5 mg OC/325 mg APAP (see selected example from Chart No. 1)in healthy subjects under fasted conditions. The PK and bioavailabilityof the extended-release formulation administered as 1 or 2 tablets werecompared to the commercially-available immediate release tablet(immediate release 7.5 mg OC/325 mg APAP) administered as 1 or 2 tabletsevery 6 hours for 2 doses. This study was conducted in 48 male andfemale subjects, with equal gender distribution.

Pharmacokinetic parameter estimates for OC are presented in Table 37,and OC plasma concentration-time profiles are presented in FIG. 21.There was no lag in absorption of OC for the 1 and 2 tablet dosingconfigurations of the extended release formulation and thecommercially-available immediate release tablet under fasted conditions.Plasma concentrations of OC rose rapidly after administration of theextended release formulation in a similar fashion to thecommercially-available immediate release tablet, and peak plasma levelsof OC were observed (T_(max)) at 4 and 3 hours for the 1 or 2 tabletdosing configuration of the extended release formulation compared with 7hours after the initial dose of 1 tablet of the commercially-availableimmediate release tablet (1 hour after the second dose) and 0.75 hoursafter the initial dose of 2 tablets of the commercially-availableimmediate release tablet. Mean plasma concentrations of OC from theextended release formulation were detectable through 36 hours in mostsubjects following all treatments and t_(1/2) was about 4 to 5 hoursacross all treatments. The extent of exposure (AUC_(0-t) andAUC_(0-inf)) for the 2 tablet dosing configuration of the extendedrelease formulation increased proportionally with dose compared with the1-tablet dosing configuration of the extended release formulation.

TABLE 37 Oxycodone Pharmacokinetic Estimates (7.5/325) Treatment CTreatment D Treatment A Treatment B Commercially- Commercially- ER ERavailable immediate available immediate Formulation Formulation releasetablet release tablet (1 tablet) (2 tablets) (1 tablet twice) (2 tabletstwice) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Parameter (N = 33) (N =33) (N = 33) (N = 27) AUC_(0-t) 87.43 (24.59) 185.98 (47.64) 191.15(53.43) 401.23 (110.56) (ng · hr/mL) AUC_(0-inf) 89.85 (24.73)^(b)187.71 (47.58) 193.10 (53.22) 403.04 (110.45) (ng · hr/mL) C_(max)(ng/mL) 8.41 (2.06) 16.39 (4.31) 20.82 (5.98) 41.24 (12.12) T_(max)(h)^(a) 4.00 (0.75-5.92) 3.00 (0.75-6.50) 7.38 (0.50-10.00) 0.75(0.50-12.00) t_(lag) (h)^(a) 0.00 (0.00-0.50) 0.00 (0.00-0.52) 0.00(0.00-0.25) 0.00 (0.00-0.25) t_(1/2) (h) 4.50 (0.78)^(b) 4.87 (0.93)4.08 (0.89) 4.34 (1.02) K_(el) (h⁻¹) 0.1590 0.1473 0.1770 0.1688(0.0307)^(b) (0.0274) (0.0352) (0.0415) ^(a)Median (minimum-maximum).^(b)N = 32

No dose-dumping was observed in any subject receiving the ERformulation. The interindividual variability (CV %) for C_(max) of OCafter administration of 1 or 2 tablets of the ER formulation wascomparable to 1 tablet of the commercially-available immediate releasetablet and less than 29% for all 3 treatments. Similarly theinterindividual variability (CV %) for AUC of OC was 28% or less for 1and 2 tablets of the ER formulation and 1 tablet of thecommercially-available immediate release tablet.

Table 38 presents APAP PK parameter estimates and FIG. 22 presents APAPplasma concentration-time profiles. The appearance of plasmaconcentrations of APAP for all dose configurations of the extendedrelease formulation and the commercially-available immediate releasetablet showed no lag. Plasma concentrations of APAP rose rapidly afteradministration of the extended release formulation, similar to thatobserved with the commercially-available immediate release tablet. Peakplasma levels of APAP following administration of the 1 tablet and 2tablet dosing configurations of the extended release formulation wereobserved (median T_(max)) at 0.75 hours after dosing compared with 0.5hours after the first dose of the commercially-available immediaterelease tablet (1 and 2 tablets). Mean plasma concentrations of APAPwere detectable through 36 hours following all treatments and the meant_(1/2) was approximately 4 to 7 hours across treatment groups. Theextent of exposure (AUC) to APAP following dosing with 1 and 2 tabletsof the extended release formulation increased proportionally with dose.

TABLE 38 APAP Pharmacokinetic Estimates (7.5/325) Treatment C TreatmentD Treatment A Treatment B Commercially- Commercially- ER ER availableimmediate available immediate Formulation Formulation release tabletrelease tablet (1 tablet) (2 tablets) (1 tablet twice) (2 tablets twice)Mean (SD) Mean (SD) Mean (SD) Mean (SD) Parameter (N = 33) (N = 33) (N =33) (N = 27) AUC_(0-t) 15871 (4841) 32665 (10894) 33040 (9589) 69837(22945) (ng · hr/mL) AUC_(0-inf) 16995 (5073) 34836 (11067)^(b) 34236(10126)^(b) 71949 (24234)^(c) (ng · hr/mL) C_(max) (ng/mL) 2632 (918)5230 (2086) 4878 (1545) 10741(4123) T_(max) (h)^(a) 0.75 (0.25-2.02)0.75 (0.25-4.00) 0.50 (0.25-9.00) 0.50 (0.25-12.00) t_(lag) (h)^(a) 0.00(0.00-0.50) 0.00 (0.00-0.25) 0.00 (0.00-0.00) 0.00 (0.00-0.00) t_(1/2)(h) 5.33 (1.53) 6.88 (2.15)6 4.41 (1.16)^(b) 5.76 (1.47)^(c) K_(el)(h⁻¹) 0.1421 0.1103 0.1669 0.1291 (0.0479) (0.0337)^(b) (0.0411)^(b)(0.0368)^(c) ^(a)Median (minimum-maximum). ^(b)N = 32 ^(c)N = 25

No dose-dumping was observed in any subject receiving the ERformulation. The interindividual variability (CV %) for C_(max) of APAPwas slightly more after administration of 1 and 2 tablets of the ERformulation (35% and 40%, respectively) than for 1 tablet of thecommercially-available immediate release tablet (32%). Theinterindividual variability (CV %) for AUC of APAP was less than 33% forall 3 treatments.

Both OC and APAP were rapidly absorbed under all conditions with no lagin plasma concentrations. Both OC and APAP levels were sufficiently highwithin 1 hour after administration of the extended release formulation.Peak exposure to OC was 18% to 21% lower for the ER formulation than forthe commercially-available immediate release tablet (1 tablet Q6h). OClevels were sustained over the proposed 12 h dosing interval. By 12hours after dosing with the extended release formulation, APAP plasmalevels were less than 20% of C_(max). Total exposure to both OC and APAPfrom the extended release formulation was equivalent to that of 1 tabletof the commercially-available immediate release tablet.

To further analyze the absorption of OC and APAP from the ERformulation, the plasma concentrations of OC and APAP followingadministration of 1 tablet of the ER formulation, 2 tablets of the ERformulation, and the commercially-available immediate release tabletwere deconvolved using WinNonlin 5.2 (Pharsight). Deconvolutionevaluates in vivo drug release and delivery based on data for a knowndrug input. Depending upon the type of reference input informationavailable, the drug transport evaluated will be either a simple in vivodrug release (e.g., gastro-intestinal release) or a composite form,typically consisting of an in vivo release followed by a drug deliveryto the general systemic circulation. It can estimate the cumulativeamount and fraction absorbed over time for the subjects, given PKprofile data and dose. For a pure immediate release (IR) or an extendedrelease (ER) formulation the cumulative absorption plot shows amonoexponential curve whereas for a bilayer formulation (IR+ER) abiexponential (rapid phase followed by slower phase) absorption curvewill be observed. FIG. 23 and FIG. 24 present the deconvolution plotsfor OC and APAP, respectively. For each, there is an early rapid phaseof absorption that is followed by a later slower phase of absorptionfrom the ER formulation.

Example 11 Clinical Pharmacokinetic Analysis of an Extended ReleaseFormulation of 7.5 mg Oxycodone/325 mg Acetaminophen—Multiple Doses

An open-label, randomized, 3-period crossover study was performed toevaluate the steady-state PK, bioavailability, and safety of theextended release formulation containing 7.5 mg OC/325 mg APAP in healthysubjects (see selected example from Chart No. 1). The PK andbioavailability of the ER formulation administered as 1 or 2 tabletsevery 12 hours for 4.5 days (9 doses) was compared to thecommercially-available immediate release tablet (immediate release 7.5mg OC/325 mg APAP) administered as 1 tablet every 6 hours for 4.5 days(18 doses) under fasted conditions (10 hours for the first dose on Days1 and 5; at least 1 hour for all other doses). This study was conductedin 48 male and female subjects, with equal gender distribution.

The PK behavior of OC on Study Day 1 (see Table 39) was similar to thatobserved in the single dose study (see Example 10). There was no lag(median t_(lag) 0 hours) in the absorption of OC followingadministration of the ER formulation (1 or 2 tablets) and thecommercially-available immediate release tablet, and no dose-dumping wasobserved for any subject. Peak plasma levels were observed at 3 hoursafter administration of 1 and 2 tablets of the ER formulation and at 1hour after the second dose of the commercially-available immediaterelease tablet (FIG. 25). On Day 1, interindividual variability (% CV)in the C_(max) for OC was slightly higher for 1 tablet (29%) than for 2tablets (23%) of the ER formulation or the commercially-availableimmediate release tablet (up to 22%). The variability in the AUC_(0-12h)for OC was comparable between all 3 treatments (21% to 23%). Minimum(trough) plasma concentrations (Cmin) of OC achieved steady-state levelsby Day 4 for 1 tablet of the ER formulation and thecommercially-available immediate release tablet and by Day 3 for 2tablets of the ER formulation. Trough levels of OC on Days 2 through 5for 2 tablets of the ER formulation were comparable to those observedfor the commercially-available immediate release tablet.

TABLE 39 Oxycodone Pharmacokinetic Estimates - Day 1 Treatment CCommercially- Treatment A Treatment B available immediate ER FormulationER Formulation release tablet (1 Tablet Q12h) (2 Tablets Q12h) (1 TabletQ6h) Mean (SD) Mean (SD) Mean (SD) Parameter (N = 33) (N = 33) (N = 33)AUC_(0-12h) 66.93 (15.14) 135.89 (30.81) 141.73 (29.78) (ng · hr/mL)C_(max) (ng/mL) 8.34 (2.37) 17.05 (3.97) 21.93 (4.80) T_(max) (h)^(a)3.00 (0.75-7.00) 3.00 (0.50-5.92) 7.00 (0.50-8.00) t_(lag) (h)^(a) 0.00(0.00-0.50) 0.00 (0.00-0.32) 0.00 (0.00-0.25) ^(a)Median(minimum-maximum).

On Day 5 (see Table 40), steady state was achieved and the medianT_(max) ^(ss) was observed at 2 hours following 1 tablet or 2 tablets ofthe ER formulation and at 30 min following the second daily dose of thecommercially-available immediate release tablet. Maximum observed plasmaconcentrations at steady-state (C_(max) ^(ss)) for OC for the 1 and 2tablet dosing configurations of the ER formulation were not equivalentto the commercially-available immediate release tablet. On Day 5,interindividual variability (% CV) in C_(max) ^(ss) and AUC₀₋₁₂ h ^(ss)for OC was comparable between all 3 treatments (up to 29%). The degreeof fluctuation (DFL) in and the swing of plasma concentrations for theER formulation over the last 12 hour dosing interval on Day 5 were 15%to 22% less than that observed for the commercially-available immediaterelease tablet.

TABLE 40 Oxycodone Pharmacokinetic Estimates - Day 5 Treatment CCommercially- available Treatment A Treatment B immediate release ERFormulation ER Formulation tablet (1 Tablet Q12 h) (2 Tablets Q12 h) (1Tablet Q6 h) Mean (SD) Mean (SD) Mean (SD) Parameter (N = 33) (N = 33)(N = 33) AUC_(0-12h) ^(ss) 102.36 (29.30) 208.59 (59.28) 208.93 (57.30)(ng · h/mL) C_(av) ^(ss) (ng/mL) 8.53 (2.44) 17.38 (4.94) 17.41 (4.78)C_(max) ^(ss) (ng/mL) 12.67 (3.48) 25.67 (7.49) 30.50 (8.91) C_(min)^(ss) (ng/mL) 4.06 (1.40) 8.98 (3.52) 8.78 (3.17) DFL (%) 101.72 (14.14)97.17 (18.80) 126.83 (27.93) Swing 2.23 (0.64) 2.03 (0.70) 2.67 (0.92)T_(max) ^(ss) (h)^(a) 2.00 (0.50-10.00) 2.00 (0.50-7.00) 6.50(0.50-8.02) t_(1/2) (h)^(c) 5.46 (1.24) 6.11 (1.46) 5.47 (1.70)^(b)K_(el) (1/h)^(c) 0.1326 (0.0269) 0.1199 (0.0291) 0.1387 (0.0418)^(b)^(a)Median (minimum-maximum). ^(b)N = 32 ^(c)Days 5 to 7.

The PK behavior of APAP on Study Day 1 (see Table 41) was similar tothat observed in the single dose study (see Example 10). Acetaminophenwas rapidly absorbed following a single dose of 1 or 2 tablets of the ERformulation and in a similar fashion to the commercially-availableimmediate release tablet (FIG. 26). There was no lag in plasmaconcentrations following any of the 3 dosing regimens (median t_(lag) 0hours), and no dose-dumping was observed for any subject. Peak APAPplasma concentrations were observed 30 to 45 minutes afteradministration of 1 or 2 tablets of the ER formulation and at 30 minutesafter the first dose of the commercially-available immediate releasetablet on Day 1. The C_(max) for APAP occurred following the first 325mg dose of the commercially-available immediate release tablet, ratherthan after the second dose. Dose proportionality for C_(max) andAUC_(0-12h) was observed over the range of 325 mg to 650 mg APAP after asingle administration of 1 or 2 tablets of the ER formulation. TheC_(min) of APAP achieved steady-state levels by Day 4 for 1 tablet andby Day 2 for 2 tablets of the ER formulation and for thecommercially-available immediate release tablet. Trough levels of APAPon Days 2 through 5 for 2 tablets of the ER formulation were comparableto those observed for the commercially-available immediate releasetablet. On Day 1, interindividual variability (% CV) in C_(max) andAUC_(0-12h) for APAP was comparable between all 3 treatments (31% orless).

TABLE 41 APAP Pharmacokinetic Estimates - Day 1 Treatment CCommercially- Treatment A Treatment B available ER ER immediateFormulation Formulation release tablet (1 Tablet Q12 h) (2 Tablets Q12h) (1 Tablet Q6 h) Mean (SD) Mean (SD) Mean (SD) Parameter (N = 33) (N =33) (N = 33) AUC_(0-12 h) 12192 (3331) 24141 (6436) 24884 (6656) (ng ·h/mL) C_(max) (ng/mL) 2631 (815) 5245 (1473) 5146 (1553) T_(max) (h)^(a)0.55 (0.25-3.00) 0.75 (0.25-2.00) 0.50 (0.25-8.00) t_(lag) (h)^(a) 0.00(0.00-0.25) 0.00 (0.00-0.25) 0.00 (0.00-0.00) ^(a)Median(minimum-maximum).

Day 5 of the study, median T_(max) ^(ss) for APAP was observed at 30minutes following 1 or 2 tablets of the ER formulation and at 30 minutesfollowing the first daily dose of the commercially-available immediaterelease tablet (see Table 42). Acetaminophen concentrations followingadministration of 325 mg or 650 mg APAP (1 or 2 tablets) Q12h wereproportional to dose. The DFL in and swing of plasma APAP levels for theER formulation were equivalent to the commercially-available immediaterelease tablet. On Day 5, interindividual variability (% CV) in C_(max)^(ss) for APAP was slightly higher following administration of 2 tabletsof the ER formulation (33%) than the % CV seen for 1 tablet of the ERformulation and the commercially-available immediate release tablet(˜27%). Interindividual variability in AUC₀₋₁₂ h ^(ss) for APAP wascomparable between all 3 treatments (up to 27%).

TABLE 42 APAP Pharmacokinetic Estimates - Day 5 Treatment CCommercially- available Treatment A Treatment B immediate release ERFormulation ER Formulation tablet (1 Tablet Q12 h) (2 Tablets Q12 h) (1Tablet Q6 h) Mean (SD) Mean (SD) Mean (SD) Parameter (N = 33) (N = 33)(N = 33) AUC_(0-12h) ^(ss) 15307 (4092) 28512 (7714) 28719 (7023) (ng ·h/mL) C_(av) ^(ss) (ng/mL) 1276 (341) 2376 (643) 2393 (585) C_(max)^(ss) (ng/mL) 3117 (840) 5872 (1932) 5968 (1639) C_(min) ^(ss) (ng/mL)474.67 (163) 870.42 (336) 922.58 (321) DFL (%) 212.08 (52.29) 218.06(81.14) 213.79 (50.53) Swing 5.95 (2.04) 6.63 (3.61) 5.94 (2.24) T_(max)^(ss) (h)^(a) 0.50 (0.25-3.00) 0.50 (0.25-3.02) 0.50 (0.25-8.02) t_(1/2)(h)^(c) 5.60 (1.35)^(b) 7.47 (2.89) 5.74 (2.98)^(b) K_(el) (1/h)^(c)0.1308 (0.0317)^(b) 0.1026 (0.0292) 0.1416 (0.0515)^(b) ^(a)Median(minimum-maximum). ^(b)N = 31 ^(c)Days 5 to 7.

Both OC and APAP were rapidly absorbed under all conditions with no lagin plasma concentrations. Both OC and APAP levels were sufficiently highwithin 1 hour after administration of the ER formulation as a singledose and at steady-state. OC levels were sustained over the proposed 12h dosing interval. Plasma APAP concentrations decreased to below 1,000ng/mL between doses of the ER formulation, thus minimizing the chancesof its accumulation and the possibility of hepatotoxicity. Totalexposure to both OC and APAP from the ER formulation was equivalent tothat of the commercially-available immediate release tablet.

Example 12 Clinical Evaluation of the Safety and Analgesic Efficacy ofan Extended Release Formulation of Oxycodone and Acetaminophen for AcutePain

Pain relief for acute post-surgical pain requires immediate-release (IR)compounds acting within 1 hour of administration. These IR compounds,however, have a short half-life and require frequent administration;this is inconvenient to patients and leads to poor compliance. Suchpatients may benefit from an extended-release (ER) oral formulation ofoxycodone hydrochloride (OC) and acetaminophen (APAP) that is designedto (1) provide the immediate-release of each drug to attain rapidtherapeutic levels (within 1 hour of dosing) and (2) provide continuousrelease of each drug to maintain the plasma levels of each drug withintherapeutic windows for sustained analgesia (up to 12 hours).Furthermore, combining analgesics with distinct mechanisms of actionprovides maximum efficacy while reducing the toxicity of each agent, asthe amount of OC and APAP can remain within the lower, safer end oftheir therapeutic windows. This ER formulation may provide theadvantages of both immediate and prolonged pain relief from twoanalgesic compounds, potentially offering greater convenience topatients and greater dosing compliance. Accordingly, a study may beconducted to demonstrate the efficacy of repeated doses of 15 mg OC/650mg APAP versus placebo, and to determine the safety and tolerability ofmultiple oral doses of the OC/APAP formulation administered to subjectswith acute postoperative, moderate to severe pain.

The study will be conducted in the following phases: 1) pre-treatmentphase consisting of a) screening, b) surgery, and c)recovery/qualification periods; 2) double-blind phase consisting of asingle dose period followed by a multiple-dose period which begins withthe request of the 2nd dose of study medication, and; 3) a voluntaryopen-label extension phase.

The single dose period of the double-blind phase will evaluate the onsetand duration of analgesia of a single dose of 15 mg OC/650 mg APAP (astwo 7.5/325 tablets) versus placebo. The time from the initial dose ofstudy medication to the onset of perceptible pain relief and to theonset of meaningful pain relief will be measured. The subject willprovide additional pain assessments (e.g., pain intensity will bemeasured using the 11 point NPRS scale at regular intervals).

The multiple dose period of the double-blind phase will evaluate theanalgesic effects of multiple doses of 15 mg OC/650 mg APAP versusplacebo with subjects dosed regularly every 12 hours for 48 hours. Themultiple dose period will begin upon administration of the second doseafter the subject's request for additional pain relief. Pain relief andintensity will be among the data measured in this arm of the study.

After completion of study evaluations 48 hours after the 2nd dose ofstudy medication, subjects will be encouraged to enter the open-labelextension phase of the study. During this time they will be providedwith doses of 15 mg OC/650 mg APAP to be taken Q12h until no longerneeded, for up to 14 days. The open-label extension phase (starting 48hours after the second dose) will evaluate the safety profile asdetermined by adverse events (AE) and evaluate subject satisfaction withanalgesic effects.

Example 13 Clinical Evaluation of the Safety and Efficacy of an ExtendedRelease Formulation of Oxycodone and Acetaminophen for Chronic Pain

An open label safety study of doses of 15 mg OC/650 mg APAP administeredat 12 hour intervals for up to 35 days in a patient population havingpain associated with osteoarthritis (OA) of the knee or hip or chroniclow back pain (CLBP) may be conducted. The primary objective of thestudy is to determine the safety and tolerability of doses of 15 mgOC/650 mg APAP for up to 35 days of use. Secondary objectives such aspain relief and changes in pain intensity will also be assessed.

Subjects enrolled in the study will be treated with 2 tablets of 7.5 mgOC/325 mg APAP every 12 hours (Q12h) for between 10 days and 35 days.Subjects will initially take 1 tablet of 7.5 mg OC/325 mg APAP underclinic supervision. Subjects will be observed for opioid tolerabilitysymptoms. Subjects who experience opioid tolerability symptoms, ormoderate to severe AEs, will be discontinued from the study. Subjectswho do not experience opioid tolerability symptoms, or moderate tosevere AEs, will be given a second tablet of 7.5 mg OC/325 mg APAP underclinic supervision. If subjects still do not experience opioidtolerability symptoms, or moderate to severe AEs, they will be sent homewith supplies for dosing with 2 tablets of 7.5 mg OC/325 mg APAP Q12hfor one week. If subjects do experience opioid tolerability symptoms, ormoderate to severe AEs, they will be sent home with supplies for dosingwith 1 tablet of 7.5 mg OC/325 mg APAP Q12h for one week.

Subjects that continue in the study beyond one week will continue totake 2 tablets Q12h for up to a total of 35 days, during which they willreturn to the clinic for subsequent assessments of safety and efficacy.After the Day 36 visit, subjects will be instructed to return topre-study medication. Subjects whose pain subsides prior to the Day 36visit, or who discontinue for other reasons will be instructed to returnremaining study medication.

Example 14 Partial Areas Under the Curve for Oxycodone and Acetaminophen

Partial AUCs were calculated for a bilayer extended release tabletdisclosed herein containing acetaminophen and oxycodone, and animmediate release acetaminophen and oxycodone tablet. Specifically,Partial AUCs were calculated for the acetaminophen and oxycodone tabletsof (1) Treatment B of Example 10, (2) Treatment C of Example 9, and (3)Treatment D of Example 10. These results are summarized in Tables 43-46.

TABLE 43 Mean (SD) Parameter Estimates for Partial AUCs forAcetaminophen. AUC_(0-1.7h) AUC_(1.7-48h) AUC_(0-t) Study (ng · h/mL)(ng · h/mL) (ng · h/mL) Treatment B (Ex. 10) 6029 28435 32644 TreatmentC (Ex. 9) 5854 25539 29741

TABLE 44 Additional Mean (SD) Parameter Estimates for Partial AUCs forAcetaminophen. AUC_(0-12h) AUC_(1-12h) AUC_(12-36h) AUC_(8-12h)AUC_(0-t) Study (ng · h/mL) (ng · h/mL) (ng · h/mL) (ng · h/mL) (ng ·h/mL) Treatment 25912 22615 7978 4401 32644 B (Ex. 10) Treatment 2410220875 6854 3910 29741 C (Ex. 9)

TABLE 45 Percent of AUC_(0-t) for Acetaminophen AUC_(12-36h) AUC_(0-12h)AUC_(1-12h) (end of dosing (dosing (T_(max) to end of interval to lastStudy interval) dosing interval) concentration) AUC_(8-12h) Treatment B79% 69% 24% 13% (Ex. 10) Treatment C 81% 70% 23% 13% (Ex. 9)

TABLE 46 Mean(SD) Parameter Estimates for Partial AUCs for Oxycodone.AUC_(0-2.8h) AUC_(2.8-48h) AUC_(0-t) Study (ng · h/mL) (ng · h/mL) (ng ·h/mL) Treatment B 28.75 158.49 185.93 (Ex. 10) Treatment C 27.89 164.27190.66 (Ex. 9)

The bioequivalence determinations between two tablets of apharmaceutical composition described herein, each containing 7.5 mgoxycodone and 325 mg acetaminophen and an immediate release tabletcomprising 7.5 mg oxycodone and 325 mg acetaminophen can be found inTables 47 and 48.

TABLE 47 Bioequivalence Determination for Acetaminophen LSM 90% ClParameter Ratio Lower Upper Ln(AUC_(0-1.7h)) 101.97 82.90 125.43Ln(AUC_(1.7-48h)) 91.15 80.58 103.11 Ln(AUC_(0-t)) 93.14 82.40 105.28

TABLE 48 Bioequivalence Determination for Oxycodone LSM 90% Cl ParameterRatio Lower Upper Ln(AUC_(0-2.8h)) 99.04 87.83 111.68 Ln(AUC_(2.8-48h))103.21 92.57 115.06 Ln(AUC_(0-t)) 102.19 92.34 113.09

The results demonstrate that the plasma concentrations of both oxycodoneand acetaminophen rose rapidly with no lag time for a pharmaceuticalcomposition of the present invention and an immediate release tabletcomprising 7.5 mg oxycodone and 325 mg acetaminophen. See FIG. 29.Further, 30 minutes after administration of a dose of a pharmaceuticalcomposition of the present invention (i.e., 2 tablets of 7.5oxycodone/325 acetaminophen), oxycodone levels were within thetherapeutic range (>5 ng/mL). Thus, an analgesic effect will be seen inopioid naïve patients. In addition, a pharmaceutical composition of thepresent invention was able to maintain oxycodone levels above 5 ng/mLfor up to 12 hours after dosing, suggesting that the analgesic effectmay extend to the next dosing cycle.

Concentrations of acetaminophen resulting from a dose of apharmaceutical composition of the present invention (i.e., 2 tablets of7.5 oxycodone/325 acetaminophen), decreased to less than 900 ng/mL (>17%of C_(max)) by 12 hours after administration. This decreasedconcentration of acetaminophen at the end of the dosing cycle allows forsufficient acetaminophen or “APAP time off” between doses.

Oxycodone and acetaminophen levels from a pharmaceutical composition ofthe present invention (i.e., 2 tablets of 7.5 oxycodone/325acetaminophen) declined at a similar rate to an immediate release tabletcomprising 7.5 mg oxycodone and 325 mg acetaminophen, with a terminalelimination half-life of approximately 4 to 5 hours.

Example 15 Partial Areas Under the Curve for Oxycodone and AcetaminophenAdministered with Food

Partial AUCs were calculated for a bilayer extended release tabletdisclosed herein containing acetaminophen and oxycodone, and animmediate release acetaminophen and oxycodone tablet. Specifically,Partial AUCs were calculated for the acetaminophen and oxycodone tabletsof (1) Treatment A of Example 4, (2) Treatment A of Example 6 (onetablet), and (3) Treatment C of Example 4. These results are summarizedin Tables 49-50.

TABLE 49 Mean (SD) Parameter Estimates for Partial AUCs forAcetaminophen. AUC_(0-3.2h) AUC_(3.2-48h) AUC_(0-t) Study (ng · h/mL)(ng · h/mL) (ng · h/mL) Treatment A (Ex. 4) 8042 23810 30245 Treatment A(Ex. 6) 9145 23319 31478 (one tablet)

TABLE 50 Mean (SD) Parameter Estimates for Partial AUCs for Oxycodone.AUC_(0-4.3h) AUC_(4.3-48h) AUC_(0-t) Study (ng · h/mL) (ng · h/mL) (ng ·h/mL) Treatment A (Ex. 4) 48.62 152.57 199.43 (15.99) (49.86) (59.47)Treatment A (Ex. 6) 53.29 167.50 219.20 (one tablet) (17.12) (51.83)(55.99)

The bioequivalence determinations between the pharmaceutical compositiondescribed herein, containing 15 mg oxycodone and 650 mg acetaminophenand an immediate release product comprising 15 mg oxycodone and 650 mgacetaminophen can be found in Tables 51 and 52.

TABLE 51 Bioequivalence Determination for Acetaminophen LSM 90% ClParameter Ratio Lower Upper Ln(AUC_(0-3.2h)) 114.46 96.21 136.16Ln(AUC_(3.2-48h)) 94.62 83.31 107.47 Ln(AUC_(0-t)) 101.32 90.00 114.07

TABLE 52 Bioequivalence Determination for Oxycodone LSM 90% Cl ParameterRatio Lower Upper Ln(AUC_(0-4.3h)) 109.87 94.98 127.08 Ln(AUC_(4.3-48h))109.75 94.48 127.48 Ln(AUC_(0-t)) 110.53 97.39 125.44

Exposure to oxycodone and acetaminophen was comparable between TreatmentA of Example 4 and Treatment A of Example 6 (one tablet). Thus, theseresults indicate that the release of oxycodone and acetaminophen isconsistent across studies. Plasma concentration-time profiles arepresented in FIGS. 30A and 30B.

The initial exposure to oxycodone (AUC_(0-4.3h)) was slightly outsidethe bioequivalence parameters established by the FDA (upper 90% CI127%). The initial exposure to acetaminophen (AUC_(0-3.2h)) was outsideof the FDA's bioequivalence parameters (upper 90% CI 136%).

The extended (sustained) exposure to oxycodone (AUC_(4.3-48h)) wasslightly outside the FDA's limit for bioequivalence (upper 90% CI 127%).However, the extended exposure to acetaminophen (AUC_(3.2-48h)) andtotal exposure (AUC_(0-t)) for both oxycodone and acetaminophen wasequivalent between studies.

Example 16 Mechanical Crushing into Powder Form

Drug abusers often tamper with extended release opioid-containingformulations by crushing the dosage form. This process generally servesseveral functions, including destroying the extended release propertiesof the dosage form and enabling the dosage form to be processed forunintended methods of administration, such as snorting or intravenousinjection. Accordingly, comparative tamper resistance experiments wereperformed on a tablet dosage form of the pharmaceutical composition ofthe present invention containing 7.5 mg oxycodone HCl and 325 mgacetaminophen (see Chart 1) (the “product”) and a commercially availableimmediate-release tablet containing 7.5 mg oxycodone/325 mgacetaminophen (the “comparator”).

The product and comparator tablets were subjected to standard mechanicalcrushing by the following means: a hammer, a pill crusher, a mortar andpestle, a knife, two spoons, a utility knife, a blender, a coffee mill,and a coffee grinder. The success or failure of the particle sizereduction was then visually assessed. In some cases, a sieving analysiswas also utilized to quantitatively measure if significant particle sizereduction occurred. Generally, drug abusers desire to crushpharmaceutical formulations into a fine powder, as this form isconvenient for processing the tablet into a snortable or injectableform.

The results demonstrated that in most instances, the comparator waseasily broken down into smaller pieces by each of the mechanical meanslisted above. Accordingly, in most instances, the comparator offeredlittle tamper resistance as it could easily be mechanically crushed intoa suitable powder. In contrast, the physical properties of the producttablet prevented the product tablet from being crushed into a finepowder. Indeed, in relation to the comparator, the product tablet wasmore difficult to break down using the methods listed above.Specifically, all of the mechanical methods described above wereineffective at producing a suitable powder from the product tabletsexcept grinding in a mortar and pestle. Consequently, the producttablets offer improved protection from the mechanical crushing methodsemployed by drug abusers.

Example 17 Abuse Resistance Properties of Product Powders Produced byGrinding Using a Mortar and Pestle

An in vitro dissolution test with human abuse liability (“HAL”)predictions was conducted to determine the cumulative amount of drugreleased from intact and crushed tablets of the pharmaceuticalcompositions disclosed herein and a commercially-available immediaterelease oxycodone and acetaminophen tablet.

Comparator tablets (the “comparator”) containing a total of 7.5 mg ofoxycodone HCl and a total of 325 mg acetaminophen were obtained. Sixcomparator tablets were ground with a mortar and pestle and placed intocapsules, while six tablets were used as is (i.e., kept intact, butplaced into capsules). Dissolution profiles for the intact and crushedtablets were determined in a USP type II apparatus. Six intact tabletsand six crushed tablets were weighed, placed in a sinker, and droppedinto an equilibrated dissolution bath vessel containing 900 mL of(helium sparged) 0.1 N HCl heated to 37° C.±0.5° C. The mixture wasstirred at 100±4 rpm, and the temperature was maintained at 37° C.±0.5°C. for 12 hr. The bath vessel was covered with a low evaporation vesselcover. Samples (5 mL) were removed at 5 min, 10 min, 20 min, 30 min, and60 min. Each sample was filtered through a 0.45 μm filter and analyzedby HPLC using standard procedures. The release profile of oxycodone HClfrom intact and crushed comparator is shown in FIG. 31.

Bilayer formulations described herein were prepared, each containing atotal of 7.5 mg of oxycodone HCl, a total of 325 mg of acetaminophen,and an extended release polymer. Six product tablets (as defined inExample 16) were ground with a mortar and pestle and placed intocapsules, while twelve product tablets were used as is. The samedissolution method as described for the intact and crushed comparatorabove was used to obtain release profiles for intact and crushed producttablets. However, six of the intact product tablets (labeled as“Intact”) were sampled (5 mL) at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6hr, 8 hr, and 12 hr. The release profiles of acetaminophen and oxycodoneHCl from the intact and crushed product tablets are shown in FIGS. 32and 33, respectively. In these figures, “intact” refers to the intactproduct tablets sampled at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8hr, and 12 hr. “HAL_Intact” refers to the intact product tablets sampledat the same time intervals as the crushed tablets, namely, 5 min, 10min, 20 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr.

These results show that for release of oxycodone HCl from the comparatortablets, there is no substantial difference in the release profiles forcrushed and intact tablets for abuse purposes. In each case, almost allof the oxycodone HCl was released in as little as ten minutes. In starkcontrast, there are substantial differences in the release profiles forcrushed and intact product tablets. The intact product tabletssurprisingly exhibited a higher release rate of both active ingredientsthan the crushed product tablets in the first hour. This suggests thatupon grinding the product tablets, the active ingredients in theimmediate release portion are incorporated into the extended releaseportion, and the product tablet loses its immediate releasecharacteristics. This feature may effectively negate a drug abuser'spurpose for crushing the product tablet in the first place—to obtain anearly onset of analgesia.

Predicted pharmacokinetic parameters were obtained for these in vitrorelease profiles for the crushed and intact products and comparatortablets by using in vitro in vivo correlation (“IVIVC”) technique. Theseresults, which are summarized in Table 53, demonstrate that the abusequotients for the crushed and intact comparator tablets are orders ofmagnitude higher than the abuse quotients for the crushed and intactproduct tablets. This is consistent with the experimentally determinedpharmacokinetic parameters from Example 10.

TABLE 53 Predicted pharmacokinetic parameters and abuse quotient forintact and crushed product and comparator tablets. Abuse QuotientProduct Cmax (ng/mL) T_(max) (hr) (ng/mL · hr) Predicted Comparator(intact) 32.5 0.16 203.1 Comparator (crushed) 30.8 0.17 181.2 Product(intact) 17.5 6 2.9 Product (crushed) 20.6 4 5.2 Experimental - seeExample 10 Comparator (intact) 41.6 0.7 59.4 Product (intact) 16.4 3.25.1

Example 18 Preconditioning the Tablets by Crisping

Drug abusers often precondition the tablet by a process known ascrisping. This procedure is intended to remove some of the tabletfillers, making the drug easier to crush and insufflate or inject.Accordingly, an experiment was performed to determine a drug abuser'sability to crisp a tablet dosage form of the pharmaceutical compositionof the present invention containing 7.5 mg oxycodone HCl and 325 mgacetaminophen (see Chart 1) (the “product”) as compared to acommercially available immediate-release tablet containing 7.5 mgoxycodone/325 mg acetaminophen (the “comparator”).

First, the product and comparator tablet were crushed into a powder andplaced in a spoon. The spoon was then heated from underneath with anopen flame. Once the powder began to caramelize and smoke, the heat wasremoved and the powder was mixed using a metal spatula. The spoon wasagain heated until the powder began to caramelize further. The heat wasonce again and removed, and the powder was allowed to cool. Theresulting powders were then removed from the spoon and placed in amortar and pestle for subsequent crushing. The comparator tabletresulted in a powder that could be easily crushed into a fine powder.Unlike the comparator tablet, the product tablet resulted in a stickycomposition, rendering the product tablet unsuitable for grinding into afine powder after the crisping process.

Example 19 Separation Studies

To determine the ease at which the immediate release (IR) and extendedrelease (ER) layers of a bilayer form of the pharmaceutical compositiondisclosed herein could be tampered with, several attempts were made atseparating the immediate release (IR) and extended release (ER) layersof the product (as defined in Example 18). Initially, a tablet dosageform of the pharmaceutical composition of the present invention waspositioned with the inscribed side facing up and cut completely throughvertically. Upon slicing the tablet, observations revealed no visualdistinction between the IR and ER layers. The tablet was thenre-oriented and sliced from several additional angles. However, nodemarcation line was observed between the IR and ER layers.Consequently, a drug abuser could not visually distinguish the IR and ERlayers of the pharmaceutical composition disclosed herein by simplycutting the dosage form.

Example 20 Injectability Studies

An injectability study was conducted to determine the extent to whichcrushed and dissolved tablets of the pharmaceutical compositiondisclosed herein containing 7.5 mg oxycodone/325 mg acetaminophen (the“product”) could be drawn into a syringe for intravenous administrationas compared to a commercially available immediate-release tabletcontaining 7.5 mg oxycodone/325 mg acetaminophen that had been crushedand dissolved (the “comparator”). Intravenous administration is a commonpractice used by drug abusers as a means to potentiate their drugs byadministering the drug as one large bolus instead of a steady releaseover time. Two measureable entities were evaluated: the amount ofuseable fluid that was harvested through the process and theconcentration of oxycodone in these aliquots. This study employed astandard 1 mL insulin syringe equipped with 22-, 26-, and 30-gaugeneedles, which are the typical sizes of needles used by intravenous drugusers.

An intact product and comparator tablet were each ground in a mortar andpestle to yield a fine powder. The powder was then placed onto atablespoon secured to a laboratory ring stand. 3 mL of deionized waterwas added to the spoon and was mixed into a slurry in an attempt todissolve the active ingredient. To enhance solubility of the drug, abutane lighter was used to uniformly heat the bottom of the spoon. Whenthe solution began to boil slightly, heat was removed and any liquidlost was replenished. A traditional insulin syringe (1 mL) with amakeshift cotton ball filter and the various gauge needles was used toextract the resulting liquid into the syringe.

Three types of cotton filters were evaluated for use in this procedure.The first filter was a small cotton plug placed between the needle huband barrel of the syringe. This filter clogged for all three gauges whenattempts were made to draw liquid into the syringe. The second filterwas formed by inserting the tip of the syringe needle into the end of aQ-tip. This second filter also prevented an appreciable amount of fluidto be drawn into the syringe. The third filter was a small piece ofcotton attached to the end of the needle. The third filter was chosenfor further study because it was the only filter evaluated in whichliquid could be drawn into the syringe for all three gauges withoutclogging the filter. The drawn liquid was collected, measured andquantified by LC/MS/MS analysis.

When water was mixed with the ground product tablet, the solid did notcompletely dissolve upon heating. Instead, a pasty material was producedthat did not readily disperse when mixed. The product required almostconstant mixing of the crushed powder and water with constant heating toproduce a removable liquid. It was difficult to generate a homogeneousmixture of liquid that could be drawn into a syringe because thecombined volume of the crushed product tablet and the 3 mL of wateressentially filled the spoon to capacity. Additionally, with heating, itwas necessary to replenish the evaporated water to maintain a constantslurry level in the spoon. Liquid samples were drawn from the bottom ofthe spoon with a 1 mL syringe with the cotton plug on the tip. Thisstudy demonstrated that only about 1 mL of liquid could consistently bedrawn into the syringe, independent of needle size. The resulting liquidin the syringe was murky and not transparent due to particulate matter.

In contrast, a large portion of the comparator readily dissolved whenmixed and heated in the tablespoon. The resulting liquid in the syringetherefore contained much less particulate matter than the liquidresulting from the product tablet.

These results indicate that injection is not a preferred form of drugdiversion for the product tablets. When adding water to the groundtablets, the user may recover only a small portion of that liquid foruse in a syringe. The product tablet tended to produce a semi-solidpaste that interfered with liquid recovery through the syringe. Theoverall results indicate a recovery of less than 20% of the oxycodone inthe product tablet.

Example 21 Snorting Studies

Another method of tampering and diversion is to grind a tablet into afine powder and insufflate (snort) the powder. The inhaled powder isdeposited inside the nasal passage, and the oxycodone is absorbedthrough the mucous membranes of the nasal passage. In order for theprocedure to work efficiently, the powder must deposit as a thin layeronto the nasal tissue in the sinus cavity. A study was performed toestimate the effectiveness of this process using the pharmaceuticalcomposition disclosed herein containing 7.5 mg oxycodone/325 mgacetaminophen (the “product”) and a commercially availableimmediate-release tablet containing 7.5 mg oxycodone/325 mgacetaminophen (the “comparator”).

Product tablet and a comparator tablet were ground in a mortar andpestle. 1 mL of water was added to each ground tablet, and the resultingcombination was mixed in an attempt to produce a thin slurry, whichmimics the interface between the nasal passage and the absorptivetissue. The product tablet formed a paste that tended to clump. Thecomparator produced a more fluid consistency. Consequently, thecomparator produced a more effective coating for absorption ofinsufflated oxycodone in the nasal cavity than the product disclosedherein.

Example 22 Dose Dumping Studies

Dose dumping is the process of releasing the active ingredient(s) of anextended release pharmaceutical formulation in a short period of time ina manner in which the entire dosage, or a significant portion of thedosage, becomes available for absorption in the body. This is oftenachieved by ingesting tablets along with alcoholic beverages to enhancedrug delivery. The alcohol serves as a means to act on either thecoating of a tablet to help release the active ingredients or to promotegreater absorption within the body. This method is employed by drugabusers as an attempt to potentiate analgesic drugs. Release of elevatedquantities of drug can lead to increased euphoric effects but can alsocause adverse effects, some of which may be fatal.

Two dissolution experiments were performed in a dose dumping study. Thedissolutions were designed to examine the differences between intactpharmaceutical compositions disclosed herein containing 7.5 mgoxycodone/325 mg acetaminophen (the “product”) and a commerciallyavailable immediate-release tablet containing 7.5 mg oxycodone/325 mgacetaminophen (the “comparator”) when exposed to simulated gastric fluiddissolution media (“SGF”). The first dissolution was performed in 75 mLof SGF in the absence of vodka. The second dissolution was performed in75 mL of a 50:50 mixture of SGF and 80-proof vodka. This was designed tomeasure the extent that the product and comparator may be abused by thesimultaneous intake of alcohol. Both dissolutions were performed at roomtemperature and were mixed on a stir plate. Aliquots were removed at0.25, 0.50, 1, 2 and 4 hours for quantification by LC/MS/MS, a summaryof which is contained in Table 54 below.

TABLE 54 Mean percent recovery of oxycodone in (i) simulatedgastrointestinal fluid and (ii) a solution containing 50% simulatedgastric fluid and 50% 80-proof vodka. Mean Percent Recovery at time = tFluid Intact Tablet 0.25 hr 0.5 hr 1 hr 2 hr 4 hr SGF Product 15% 30%43% 57% 80% SGF Comparator 104% 102% 105% 102% 100% SGF:EtOH Product 12%23% 35% 46% 62% SGF:EtOH Comparator 101% 101% 103% 100% 102%

At the end of the four hour dissolution, the product tablets were stillvisible but had lost their outer coating in SGF both in the presence andabsence of vodka. Addition of ethanol to the SGF produced a slightdecrease in the dissolution rate of the product tablet. Comparatortablets were dissolved in SGF both in the presence and absence of vodkaafter five minutes. Consequently, the product tablets were resistant todose dumping when compared to the comparator tablets.

Example 23 Clinical Evaluation of the Relative Abuse Potential of anExtended Release Formulation of Oxycodone and Acetaminophen

A study may be performed to assess the relative abuse potential of abilayer, extended-release oral formulation disclosed herein containing7.5 mg oxycodone/325 mg acetaminophen (see Chart One) versus animmediate release oxycodone HCl/acetaminophen tablet in non-dependent,recreational opioid users. The study will consist of a screening period,and in-clinic period, and a follow-up period.

The study will consist of seven treatment periods, each of which willinvolve a single treatment of one of the study medications followed by awash-out period. Tests will be conducted to ensure that the subjects arenot physically dependent on opioids, and that they can discriminatebetween the effects oxycodone versus the placebo. Upon completion, thestudy medications will be randomly administered as a single oral dose toeach subject and consist of the following:

Group A: two tablets disclosed herein containing 7.5 mg oxycodone HCland 325 mg acetaminophen each plus two placebo tablets disclosed hereinplus four placebo immediate release capsules.

Group B: four tablets disclosed herein containing 7.5 mg oxycodone HCland 325 mg acetaminophen each plus four placebo immediate releasecapsules.

Group C: two immediate release capsules containing 7.5 mg oxycodone HCland 325 mg acetaminophen each plus two placebo immediate releasecapsules plus four placebo tablets disclosed herein.

Group D: four immediate release capsules containing 7.5 mg oxycodone HCland 325 mg acetaminophen each plus four placebo tablets disclosedherein.

Group E: two crushed tablets disclosed herein containing 7.5 mgoxycodone HCl and 325 mg acetaminophen each placed in four capsules plusfour placebo tablets disclosed herein.

Group F: two crushed immediate release tablets containing 7.5 mgoxycodone HCl and 325 mg acetaminophen each placed in two capsules plustwo placebo immediate release capsules.

Group G: four placebo tablets disclosed herein plus four placeboimmediate release capsules.

Subjects will receive seven treatments according to their treatmentsequence, and doses will be separated.

Example 24 Varying Polyox Grades Comprising 25% by Weight of theExtended Release Portion of Bilayer Formulations

Single layer tablet formulations containing only the extended releaseportion were prepared, each tablet containing a total of 9 mg ofoxycodone HCl and a total of 250 mg of acetaminophen. Since thesetablets contained only the extended release portion, they contained 50%of the total acetaminophen for the bilayer tablet and 60% of the totaloxycodone HCl for the bilayer tablet. In a first formulation, POLYOX®205 was employed as the extended release component in an amount of 25%by weight of the ER portion, and therefore, the tablet weight. In asecond formulation, POLYOX® 1105 was employed as the extended releasecomponent in an amount of 25% by weight of the tablet of ER portion. Ina third formulation, POLYOX® N-60K was employed as the extended releasecomponent in an amount of 25% by weight of the tablet or ER portion.

Dissolution profiles for the three above-described compositions weredetermined in USP Type II apparatus. Six tablets of each compositionwere weighed, placed in a sinker, and dropped into an equilibrateddissolution bath vessel containing 900 mL of (helium sparged) 0.1 N HClheated to 37° C.±0.5° C. The mixture was stirred at 150±6 rpm, and thetemperature was maintained at 37° C.±0.5° C. through 12 hr. The bathvessel was covered with a low evaporation vessel cover. Samples (5 mL)were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6, hr, 8 hr, and 12hr. The final time point for the Polyox 205 was 17 hrs; the final timepoint for the Polyox 1105 was 15 hrs; and the final time point for thePolyox N60k was 18 hrs and 40 minutes. Each sample was filtered througha 0.45 μm filter and analyzed by HPLC using standard procedures.

The cumulative release profiles of acetaminophen and oxycodone fromthese compositions are shown in FIGS. 34 and 35, respectively. This datarepresents dissolution for the extended release portion with theimmediate release data theoretically added. These figures demonstratethat as the average molecular weight of the POLYOX® extended releasecomponent increases, the rate of dissolution at each time pointdecreases. For example, the formulations containing POLYOX® 205, 1105,and N-60K had released about 59%, about 56%, and about 55% acetaminophenafter 15 minutes, respectively; about 63%, about 59%, and about 57%acetaminophen after 30 minutes, respectively; about 69%, about 64%, andabout 61% acetaminophen after 1 hr, respectively; about 78%, about 73%,and about 67% acetaminophen after 2 hr, respectively; about 91%, about87%, and about 76% acetaminophen after 4 hr, respectively; about 97%,about 95%, and about 84% acetaminophen after 6 hr, respectively; andabout 98%, about 97%, and about 90% acetaminophen after 8 hr,respectively.

The same general trend of a decreased release rate with a highermolecular weight POLYOX® grade was also observed for the oxycodone. Forexample, the formulations containing POLYOX® 205, 1105, and N-60K hadreleased about 53%, about 50%, and about 48% oxycodone after 15 minutes,respectively; about 60%, about 56%, and about 53% oxycodone after 30minutes, respectively; about 68%, about 63%, and about 59% oxycodoneafter 1 hr, respectively; about 80%, about 75%, and about 67% oxycodoneafter 2 hr, respectively; about 94%, about 91%, and about 80% oxycodoneafter 4 hr, respectively; about 100%, about 98%, and about 89% oxycodoneafter 6 hr, respectively; and about 100%, about 99%, and about 95%oxycodone after 8 hr, respectively.

Example 25 Varying Polyox Grades Comprising 45% by Weight of theExtended Release Portion of Bilayer Formulations

Single layer formulations containing only the extended release portiondescribed herein were prepared, each tablet containing a total of 9 mgof oxycodone HCl and a total of 250 mg of acetaminophen. Since thesetablets contained only the extended release portion, they contained 50%of the total acetaminophen for a bilayer tablet and 60% of the totaloxycodone HCl for a bilayer tablet. In a first formulation, POLYOX® 205was employed as the extended release component in an amount of 45% byweight of the tablet or ER portion. In a second formulation, POLYOX®1105 was employed as the extended release component in an amount of 45%by weight of the tablet or ER portion. In a third formulation, POLYOX®N-60K was employed as the extended release component in an amount of 45%by weight of the tablet or ER portion. The other excipients in theextended release portion were microcrystalline cellulose, spress B825,citric acid anhydrous, EDTA, hydroxypropyl cellulose, silicon dioxide,and magnesium stearate.

Dissolution profiles for the three above-described formulations wereDetermined in USP Type II apparatus. Six tablets of each formulationwere weighed, placed in a sinker, and dropped into an equilibrateddissolution bath vessel containing 900 mL of (helium sparged) 0.1 N HClheated to 37° C.±0.5° C. The mixture was stirred at 150±6 rpm, and thetemperature was maintained at 37° C.±0.5° C. through 12 hr. The bathvessel was covered with a low evaporation vessel cover. Samples (5 mL)were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6, hr, 8 hr, and 12hr. The final time point for the Polyox 205 was 17 hours; the final timepoint for Polyox 1105 was 17.5 hours; and the final time point forPolyox N60k was 23.5 hours. Each sample was filtered through a 0.45 μmfilter and analyzed by HPLC using standard procedures.

The cumulative release profiles of acetaminophen and oxycodone fromthese compositions are shown in FIGS. 36 and 37, respectively. This datarepresents dissolution for the extended release portion with theimmediate release data theoretically added. Consistent with the resultsof Example 24, the rate of dissolution at each time point decreases asthe molecular weight of POLYOX® increases. For example, the formulationscontaining POLYOX® 205, 1105, and N-60K had released about 53%, about53%, and about 53% acetaminophen after 15 minutes, respectively; about56%, about 55%, and about 54% acetaminophen after 30 minutes,respectively; about 61%, about 60%, and about 57% acetaminophen after 1hr, respectively; about 70%, about 67%, and about 63% acetaminophenafter 2 hr, respectively; about 85%, about 81%, and about 71%acetaminophen after 4 hr, respectively; about 95%, about 90%, and about79% acetaminophen after 6 hr, respectively; about 99%, about 95%, andabout 85% acetaminophen after 8 hr, respectively; and about 99%, about96% and about 93% acetaminophen after 12 hr.

The formulations containing POLYOX® 205, 1105, and N-60K also releasedabout 47%, about 47%, and about 46% oxycodone after 15 minutes,respectively; about 51%, about 50%, and about 49% after 30 minutes,respectively; about 59%, about 56%, and about 53% oxycodone after 1 hr,respectively; about 70%, about 67%, and about 62% oxycodone after 2 hr,respectively; about 88%, about 83%, and about 74% oxycodone after 4 hr,respectively; about 99%, about 93%, and about 83% oxycodone after 6 hr,respectively; and about 100%, about 97%, and about 90% oxycodone after 8hr, respectively.

Example 26 Varying the Concentrations of a Specific Polyox Grade in theExtended Release Portion of Bilayer Formulations

The data from Examples 24 and 25 indicate that an increase in the amountof POLYOX® in the pharmaceutical composition retards the release ofoxycodone and acetaminophen from the pharmaceutical composition. Toconfirm this observation, single layer extended release formulationsdescribed herein were prepared, each containing a total of 9 mg ofoxycodone HCl and a total of 250 mg of acetaminophen. Since thesetablets contained only the extended release portion, they contained 50%of the total acetaminophen for the bilayer tablet and 60% of the totaloxycodone for the bilayer tablet. In a first formulation, POLYOX® 1105was employed as the extended release component in an amount of 25% byweight of the tablet or ER portion. In a second formulation, POLYOX™1105 was employed as the extended release component in an amount of 35%by weight of the tablet or ER portion. In a third formulation, POLYOX™1105 was employed as the extended release component in an amount of 45%by weight of the tablet or ER portion. In a fourth formulation, POLYOX®1105 was employed as the extended release component in an amount of 55%by weight of the tablet or ER portion. The amount of themicrocrystalline cellulose in the four formulations was adjusted toaccount for the differing amounts of POLYOX® 1105 in each formulation.The other excipients in the extended release portion were B825, citricacid anhydrous, EDTA, hydroxypropyl cellulose, silicon dioxide, andmagnesium stearate. However, the percentages for all the otherexcipients remained the same for each formulation, and were consistentwith the percentages used in Example 25.

Dissolution profiles for the above-described formulations weredetermined in USP Type II apparatus. Six tablets of each formulationwere weighed, placed in a sinker, and dropped into an equilibrateddissolution bath vessel containing 900 mL of (helium sparged) 0.1 N HClheated to 37° C.±0.5° C. The mixture was stirred at 150±6 rpm, and thetemperature was maintained at 37° C.±0.5° C. through 12 hr. The bathvessel was covered with a low evaporation vessel cover. Samples (5 mL)were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6, hr, 8 hr, and 12hr. The final time point for the 25%, 35%, 45%, and 55% formulations was15 hr, 15 hr, 17.5 hr, and 17.5 hr, respectively. Each sample wasfiltered through a 0.45 μm filter and analyzed by HPLC using standardprocedures.

The cumulative release profiles of acetaminophen and oxycodone fromthese compositions are shown in FIGS. 38 and 39, respectively. Theseprofiles confirm that as the amount of POLYOX® 1105 used in thepharmaceutical formulations increase, the release rate of theacetaminophen and oxycodone generally decreases. For example, theformulations containing 25%, 45%, and 55% POLYOX® 1105 had releasedabout 56%, about 53%, and about 53% acetaminophen after 15 minutes,respectively; about 59%, about 56%, about 55%, and about 55%acetaminophen after 30 minutes, respectively; about 64%, about 61%,about 60%, and about 59% acetaminophen after 1 hr, respectively; about73%, about 70%, about 67%, and about 66% acetaminophen after 2 hr,respectively; about 87%, about 84%, about 81%, and about 79%acetaminophen after 4 hr, respectively; about 95%, about 93%, about 90%,and about 89% acetaminophen after 6 hr, respectively; about 97%, about97%, about 95%, and about 95% acetaminophen after 8 hr, respectively;and about 97%, about 97%, about 96%, and about 98% acetaminophen after12 hr, respectively.

Similar trends were observed for the cumulative release of oxycodone.However, there was no observable difference in the release of oxycodonefrom the formulations containing 45% and 55% POLYOX® 1105. For example,the formulations containing 25%, 45%, and 55% POLYOX® 1105 had releasedabout 50%, about 47%, and about 45% oxycodone after 15 minutes,respectively; about 56%, about 51%, about 50%, and about 50% oxycodoneafter 30 minutes, respectively; about 63%, about 58%, about 56%, andabout 56% oxycodone after 1 hr, respectively; about 75%, about 70%,about 67%, and about 66% oxycodone after 2 hr, respectively; about 91%,about 87%, about 83%, and about 82% oxycodone after 4 hr, respectively;about 98%, about 96%, about 93%, and about 93% oxycodone after 6 hr,respectively; about 99%, about 99%, about 97%, and about 98% oxycodoneafter 8 hr, respectively; and about 99%, about 100%, about 97%, andabout 100% oxycodone after 12 hr, respectively.

Example 27 In Vitro Dissolution of Controlled-Release Bilayer TabletsContaining 7.5 mg Oxycodone and 325 mg Acetaminophen Performed at a 100rpm Paddle Speed

Three batches of bilayer formulations described herein were prepared,each containing a total of 7.5 mg of oxycodone HCl and a total of 325 mgof acetaminophen. 50% of the acetaminophen was contained in theimmediate release portion, and the other 50% was contained in the ERlayer. 25% of the oxycodone HCl was contained in the immediate releaseportion of the formulation, and the other 75% was contained in the ERlayer. POLYOX® 1105 was employed as the extended release component in anamount of 45% by weight of the ER portion.

Dissolution profiles for the formulations of each batch were determinedin a USP Type II apparatus. Twelve tablets from each batch were weighed,placed in a sinker, and dropped into an equilibrated dissolution bathvessel containing 900 mL of (helium sparged) 0.1 N HCl heated to 37°C.±0.5° C. The mixture was stirred at 100±4 rpm, and the temperature wasmaintained at 37° C.±0.5° C. for 12 hr. The bath vessel was covered witha low evaporation vessel cover. Samples (5 mL) were removed at 0.25 hr,0.5 hr, 1 hr, 2 hr, 4 hr, 6, hr, 8 hr, and 12 hr. Each sample wasfiltered through a 0.45 μm filter and analyzed by HPLC using standardprocedures.

The cumulative percent release of acetaminophen and oxycodone from eachbatch are described in Table 55.

TABLE 55 Release rate data of bilayer tablets (7.5 mg oxycodone HCI; 325mg acetaminophen) using a 100 rpm dissolution method. Time Oxycodone HCIAcetaminophen (Hours) Mean (%) RSD Min (%) Max (%) Mean (%) RSD Min (%)Max (%) Batch 1 0.25 31.7 2.1 30.6 32.5 51.8 1.4 50.9 53.1 0.5 37.1 1.336.3 37.8 54.3 1.3 53.5 55.6 1.0 45.4 1.0 44.9 46.0 58.6 1.2 57.7 60.12.0 58.5 1.3 57.4 59.7 66.0 1.2 64.8 67.7 4.0 78.6 1.7 76.8 80.5 78.51.5 77.0 80.6 6.0 92.2 1.8 90.0 94.7 88.0 1.6 86.0 90.3 8.0 99.5 1.897.4 102.7 93.8 1.5 91.8 96.3 12.0 101.7 1.4 99.7 104.3 96.1 1.0 94.998.2 Batch 2 0.25 31.6 3.5 29.6 34.0 52.1 4.0 48.8 55.8 0.5 37.2 3.234.9 39.9 54.5 3.8 51.4 58.3 1.0 45.4 3.3 42.4 48.3 59.1 3.5 56.0 63.12.0 58.9 1.7 57.3 61.1 66.4 3.0 63.6 70.0 4.0 79.1 1.5 77.7 81.5 78.72.5 75.4 81.8 6.0 93.1 1.3 91.5 95.8 87.7 2.2 84.4 90.7 8.0 100.2 1.298.7 102.3 93.5 1.9 90.4 96.2 12.0 102.7 1.3 100.4 104.4 95.6 2.0 92.698.4 Batch 3 0.25 30.4 1.6 29.3 31.0 52.2 2.3 49.6 54.2 0.5 35.7 1.634.2 36.7 54.6 2.3 52.0 56.6 1.0 43.5 1.8 42.0 45.1 58.6 2.2 56.0 60.82.0 56.1 1.9 54.4 58.0 65.5 2.1 63.1 68.0 4.0 75.4 1.8 73.3 77.6 77.32.0 74.8 80.0 6.0 88.9 1.7 86.1 91.4 86.5 2.2 83.7 90.1 8.0 97.0 1.594.7 99.8 93.0 2.1 90.1 96.8 12.0 100.4 1.1 98.7 102.4 96.5 1.6 93.298.3

Example 28 In Vitro Dissolution of Controlled-Release Bilayer TabletsContaining 15 mg Oxycodone and 650 mg Acetaminophen Performed at a 150rpm Paddle Speed

Bilayer formulations described herein were prepared, each containing atotal of 15 mg of oxycodone HCl and a total of 650 mg of acetaminophen.50% of the acetaminophen was contained in the immediate release portion,and the other 50% was contained in the ER layer. 25% of the oxycodoneHCl was contained in the immediate release portion of the formulation,and the other 75% was contained in the ER layer. POLYOX® 1105 wasemployed as the extended release component in an amount of 45% by weightof the ER portion.

Dissolution profiles for the formulations were determined in a USP TypeII apparatus. Six tablets were weighed, placed in a sinker, and droppedinto an equilibrated dissolution bath vessel containing 900 mL of(helium sparged) 0.1 N HCl heated to 37° C.±0.55° C. The mixture wasstirred at 150±6 rpm, and the temperature was maintained at 37° C.±0.5°C. for 12 hr. The bath vessel was covered with a low evaporation vesselcover. Samples (5 mL) were removed at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr,6, hr, 8 hr, and 12 hr. Each sample was filtered through a 0.45 μmfilter and analyzed by HPLC using standard procedures.

The cumulative percent release of acetaminophen and oxycodone from eachbatch are described in Table 56.

TABLE 56 Release rate data of bilayer tablets (15 mg oxycodone HCl; 325mg acetaminophen) using a 150 rpm dissolution method. Time (hr)Oxycodone HCl (%) Acetaminophen (%) 0.25 33.7 54.4 0.50 39.0 56.5 1 47.460.6 2 61.4 68.1 4 81.7 81.1 6 95.2 90.8 8 101.2 96.0 12 102.3 97.6

Example 29 Ethanol Release Testing at a 100 rpm Paddle Speed

The ethanol release studies discussed above in Example 8 were repeated,except that the solutions were stirred at a paddle speed of 100 rpm andadditional aliquots were sampled at 240 min and 480 min. Tables 57, 58,59, 60, and 61 present the percent release of OC and APAP in thepresence of 0%, 5%, 10%, 20%, and 40% ethanol, respectively. FIG. 40presents dissolution profiles for OC and FIG. 41 presents dissolutionprofiles for APAP in the presence of 0%, 5%, 20%, and 40% ethanol. Likethe results at a paddle speed of 150 rpm, these data reveal that, forboth OC and APAP, the dissolution in 5%, 20%, or 40% ethanol was eithercomparable or slower than the dissolution in 0% ethanol, indicating nodose dumping for this formulation.

TABLE 57 Percent Release in 0% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 32.5 3.7 31.5 36.0 52.21.6 50.7 53.4 30 37.6 2.5 36.6 39.9 54.6 1.4 53.2 55.7 45 42.1 2.7 40.944.8 56.8 1.4 55.3 57.9 60 45.8 2.1 44.6 48.1 58.8 1.4 57.4 59.8 75 49.62.3 48.2 52.2 60.8 1.4 59.2 61.8 90 53.1 2.4 51.7 55.8 62.6 1.4 60.963.8 105 56.3 2.4 54.8 59.3 64.3 1.4 62.6 65.6 120 59.5 2.5 57.6 63.066.0 1.4 64.2 67.3 240 80.3 2.5 77.3 84.9 78.6 1.8 76.3 80.6 480 102.41.8 100.5 107.2 95.5 1.6 92.6 97.7

TABLE 58 Percent Release in 5% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 31.5 2.5 30.0 32.9 52.62.1 51.4 55.1 30 36.8 2.4 35.6 38.5 55.1 2.0 53.8 57.6 45 40.9 2.8 38.943.5 57.1 2.0 55.8 59.6 60 44.6 3.7 42.1 48.4 58.9 2.0 57.6 61.4 75 48.03.6 46.0 52.6 60.7 1.9 59.4 63.2 90 51.0 3.1 49.3 55.3 62.3 1.9 61.064.7 105 54.3 3.2 51.8 58.6 63.9 2.0 62.6 66.4 120 57.1 3.2 54.6 61.765.5 1.9 64.1 67.8 240 76.6 3.2 73.8 83.0 77.2 2.1 75.5 80.6 480 99.92.7 95.8 106.8 94.4 1.7 92.6 98.1

TABLE 59 Percent Release in 10% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 30.3 3.1 28.9 32.1 51.71.8 50.1 53.4 30 35.6 3.3 33.7 37.3 54.1 1.9 52.4 55.8 45 39.6 2.6 37.640.9 56.0 1.9 54.3 57.8 60 43.1 2.6 41.2 44.7 57.8 1.9 56.1 59.5 75 46.22.3 44.1 47.5 59.5 1.8 57.7 61.1 90 49.3 2.1 47.3 50.6 61.1 1.8 59.362.8 105 52.2 2.2 50.1 53.6 62.6 1.8 60.9 64.2 120 54.8 2.3 52.8 56.464.1 1.8 62.3 65.6 240 73.8 2.2 70.8 76.1 75.5 1.7 73.4 77.4 480 98.42.1 94.7 101.1 93.5 1.6 91.0 95.9

TABLE 60 Percent Release in 20% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 28.0 6.0 23.9 30.3 50.25.1 43.0 53.0 30 33.6 4.5 30.7 35.6 53.4 3.1 49.5 55.9 45 37.9 2.9 35.739.6 55.5 2.6 52.6 57.9 60 41.2 3.1 39.2 43.2 57.3 2.3 55.1 59.8 75 44.12.9 42.3 46.6 59.0 2.2 57.0 61.4 90 46.5 3.5 42.7 49.1 60.5 2.1 58.662.9 105 49.8 2.9 48.0 52.8 61.9 2.1 60.2 64.4 120 52.2 2.8 49.9 54.863.3 2.0 61.7 65.9 240 72.2 2.1 69.4 74.7 76.0 1.7 74.1 78.4 480 95.72.3 91.7 98.7 91.9 1.7 89.3 94.6

TABLE 61 Percent Release in 40% Ethanol OC APAP Time Min- Max- Min- Max-(Min) Mean RSD imum imum Mean RSD imum imum 15 11.9 13.9 10.0 15.1 16.723.2 12.3 22.9 30 21.1 15.4 17.3 26.2 30.4 22.3 21.7 40.7 45 26.8 11.622.4 30.3 38.5 15.3 29.6 44.8 60 30.8 7.0 26.8 34.0 43.1 9.2 35.9 47.175 34.2 5.0 31.5 36.8 46.1 5.3 41.1 49.2 90 36.9 3.2 35.1 38.8 48.3 3.344.6 50.2 105 39.6 3.3 37.3 41.2 49.8 2.4 47.3 51.3 120 41.9 3.3 39.444.2 51.1 2.3 48.3 52.7 240 57.0 1.8 55.7 58.9 60.8 2.0 58.9 63.6 48080.6 1.6 78.4 83.7 77.2 1.3 75.7 78.7

All references cited herein are hereby incorporated by reference. Theforegoing is offered primarily for purposes of illustration. It will bereadily apparent to those skilled in the art that further drugs can beincluded, and that the shapes, components, additives, proportions,methods of formulation, and other parameters described herein can bemodified further or substituted in various ways without departing fromthe spirit and scope of the invention.

What is claimed:
 1. A pharmaceutical composition comprising: (a) atleast one immediate release portion comprising about 125 mg to about 325mg of acetaminophen and about 1.5 mg to about 4.0 mg oxycodone or apharmaceutically acceptable salt thereof; and (b) at least one extendedrelease portion comprising about 125 mg to about 325 mg of acetaminophenand about 4.5 mg to about 6.5 mg oxycodone or salt thereof, and anextended release component; wherein the total amount of acetaminophen inthe composition is about 325 mg to about 650 mg, and the total amount ofoxycodone or salt in the composition is about 7.5 mg to about 10 mg,wherein upon placement of the composition in an in vitro dissolutiontest comprising USP Paddle Method at a paddle speed of about 100 rpm in900 mL of 0.1N HCl using a USP type II apparatus at a constanttemperature of about 37° C., about 25% to about 35% of the total amountof oxycodone or salt thereof in the composition is released at about 15minutes in the test and about 50% to about 55% of the total amount ofacetaminophen in the composition is released at about 15 minutes in thetest.
 2. The pharmaceutical composition of claim 1, wherein upon oraladministration of a single dose of the composition to a subject, thecomposition provides a C_(max) for oxycodone from about 0.9 ng/mL/mg toabout 1.6 ng/mL/mg, a C_(max) for acetaminophen from about 4.0 ng/mL/mgto about 11.0 ng/mL/mg, a T_(max) for oxycodone from about 2 hours toabout 7 hours, and a T_(max) for acetaminophen from about 0.5 hour toabout 6 hours.
 3. The pharmaceutical composition of claim 1, whereinfrom about 50% to about 65%, by weight, of the oxycodone or salt isreleased from the composition at about 2 hours in the test, from about70% to about 85%, by weight, of the oxycodone or salt is released fromthe composition at about 4 hours in the test, from about 90% to about100%, by weight, of the oxycodone or salt is released from thecomposition at about 8 hours in the test, from about 60% to about 75%,by weight, of the acetaminophen is released from the composition atabout 2 hours in the test, and from about 75% to about 85%, by weight,of the acetaminophen is released from the composition at about 4 hoursin the test.
 4. The pharmaceutical composition of claim 1, wherein uponoral administration of multiple doses to a subject in need of analgesia,the composition produces a blood plasma profile characterized by a meanAUC for oxycodone from about 12.0 ng·hr/mL/mg to about 16.0 ng·hr/mL/mg,a steady state AUC for oxycodone from about 13.0 ng·hr/mL/mg to about15.0 ng·hr/mL/mg, a mean AUC for acetaminophen from about 35.0ng·hr/mL/mg to about 80.0 ng·hr/mL/mg, and a steady state AUC foracetaminophen from about 37.0 ng·hr/mL/mg to about 42.0 ng·hr/mL/mg. 5.The pharmaceutical composition of claim 1, wherein upon oraladministration of multiple doses to a subject in need of analgesia, thecomposition produces a blood plasma profile characterized by a medianT_(max) for oxycodone from about 3.0 hours to about 6.0 hours, a steadystate T_(max) for oxycodone from about 2.0 hours to about 3.0 hours, amedian T_(max) for acetaminophen from about 1.0 hour to about 5.0 hours,and a steady state T_(max) for acetaminophen from about 0.5 hour toabout 1.0 hours.
 6. The pharmaceutical composition of claim 1, whereinupon placement of the composition in an in vitro dissolution testcomprising USP Paddle Method at a paddle speed of about 100 rpm in 900mL of 0.1N HCl using a USP type II apparatus at a constant temperatureof about 37° C., about 34% to about 40% of the oxycodone or salt thereofis released at about 30 minutes in the test and about 51% to about 58%of the acetaminophen is released at about 30 minutes in the test.
 7. Thepharmaceutical composition of claim 1, wherein the extended releasecomponent comprises polyethylene oxide.
 8. The pharmaceuticalcomposition of claim 7, wherein the polyethylene oxide has a molecularweight from about 500,000 Daltons to about 10,000,000 Daltons.
 9. Thepharmaceutical composition of claim 1, wherein the at least oneimmediate release portion comprises from about 20% to about 30% of thetotal amount of oxycodone in the composition and from about 40% to about60% of the total amount of acetaminophen in the composition, and the atleast one extended release portion comprises the balance of each ofoxycodone and acetaminophen.
 10. The pharmaceutical composition of claim1, wherein the immediate release portion comprises, by weight of theimmediate release portion, from about 70% to about 80% acetaminophen andfrom about 0.5% to about 1% of oxycodone; and the extended releaseportion comprises, by weight of the extended release portion, from about30% to about 50% of the extended release component, from about 20% toabout 40% of acetaminophen, and from about 0.5% to about 2% ofoxycodone.
 11. The pharmaceutical composition of claim 1, wherein theextended release component comprises a polymer selected from the groupconsisting of linear, branched, dendrimeric, or star polymers,hydrophilic polymers, and mixtures thereof.
 12. The pharmaceuticalcomposition of claim 1, wherein the extended release component comprisesa polymer selected from the group consisting of a polyalkylene oxide,poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide)poly(propylene oxide), methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystallinecellulose, acrylic acid, methacrylic acid, methyl acrylate, ethylacrylate, methyl methacrylate, ethyl methacrylate, aminoethyl acrylate,maleic anhydride copolymer, polymaleic acid, poly(acrylamide),poly(methacrylamide), poly(dimethylacrylamide),poly(N-isopropyl-acrylamide), poly(olefinic alcohol), poly(vinylalcohol), poly(N-vinyl lactam), poly(vinyl pyrrolidone), poly(N-vinylcaprolactam), polyol, glycerol, polyglycerol, propylene glycol,trimethylene glycol, mono-, di- and tri-polyoxyethylated glycerol, mono-and di-polyoxyethylated propylene glycol, mono- and di-polyoxyethylatedtrimethylene glycol, polyoxyethylated sorbitol, polyoxyethylatedglucose, polyoxazolines, poly(methyloxazoline), poly(ethyloxazoline),polyvinylamine, polyvinylacetate, ethylene-vinyl acetate copolymer,polyvinyl acetate phthalate, polyimines, polyethyleneimine, starch,starch-based polymer, polyurethane hydrogel, chitosan, polysaccharidegums, xanthan gum, zein, shellac, ammoniated shellac, shellac-acetylalcohol, shellac n-butyl stearate, and mixtures thereof.
 13. Apharmaceutical composition comprising: (a) at least one immediaterelease portion comprising about 125 mg to about 325 mg of acetaminophenand about 1.5 mg to about 4.0 mg oxycodone or a pharmaceuticallyacceptable salt thereof; and (b) at least one extended release portioncomprising about 125 mg to about 325 mg of acetaminophen and about 4.5mg to about 6.5 mg oxycodone or salt thereof, and an extended releasecomponent; wherein the total amount of acetaminophen in the compositionis about 325 mg to about 650 mg, and the total amount of oxycodone orsalt in the composition is about 7.5 mg to about 10 mg; wherein uponplacement of the composition in an in vitro dissolution test comprisingUSP Paddle Method at a paddle speed of about 150 rpm in 900 mL of 0.1NHCl using a USP type II apparatus at a constant temperature of about 37°C., the drug release profile substantially corresponds to the following:after 15 minutes, no more than about 35%, by weight, of the total amountof the oxycodone or salt is released and no more than about 55%, byweight, of the total amount of the acetaminophen is released; after 1hour, no more than about 50%, by weight, of the total amount of theoxycodone or salt is released and no more than about 63%, by weight, ofthe total amount of the acetaminophen is released; after 2 hours, nomore than about 65%, by weight, of the total amount of the oxycodone orsalt is released and no more than about 75%, by weight, of the totalamount of the acetaminophen is released; after 4 hours, from about 65%to about 85%, by weight, of the total amount of the oxycodone or salt isreleased and from about 70% to about 90%, by weight, of the total amountof the acetaminophen is released; after 8 hours, from about 85% to about100%, by weight, of the total amount of the oxycodone or salt isreleased and from about 85% to about 100%, by weight, of the totalamount of the acetaminophen is released; and after 12 hours, from about95% to about 100%, by weight, of the total amount of the oxycodone orsalt is released and from about 90% to about 100%, by weight, of thetotal amount of the acetaminophen is released.
 14. The pharmaceuticalcomposition of claim 13, wherein the composition comprises about 325 mgof acetaminophen and about 7.5 mg of oxycodone.
 15. The pharmaceuticalcomposition of claim 13, wherein when orally administered to a subject,the composition produces a blood plasma concentration profilecharacterized by a biphasic increase in blood plasma concentrations ofoxycodone and acetaminophen.
 16. The pharmaceutical composition of claim15, wherein the biphasic increase in blood plasma concentrations ofoxycodone is characterized by a plasma concentration-time profile foroxycodone in which the slope of a line drawn between 0 hour and about 2hours is greater than the slope of a line drawn between about 2 hoursand about 5 hours.
 17. A pharmaceutical composition as a solid oraldosage form comprising: (a) at least one immediate release portioncomprising about 125 mg to about 325 mg of acetaminophen and about 1.5mg to about 4.0 mg oxycodone or a pharmaceutically acceptable saltthereof; and (b) at least one extended release portion comprising about125 mg to about 325 mg of acetaminophen and about 4.5 mg to about 6.5 mgoxycodone or salt thereof, and an extended release component; whereinthe total amount of acetaminophen in the composition is about 325 mg,and the total amount of oxycodone or salt in the composition is about7.5 mg; wherein upon oral administration of two solid oral dosage formsof the composition in multiple doses in an amount of about 15 mgoxycodone or salt and about 650 mg acetaminophen, the compositionprovides an AUC_(0-1.7h) for acetaminophen of about 5.0 ng·h/mL/mg toabout 13.0 ng·h/mL/mg; an AUC_(1.7-48h) for acetaminophen of about 25.0ng·h/mL/mg to about 75.0 ng·h/mL/mg, an AUC_(0-2.8h), for oxycodone orsalt of about 1.0 ng h/mL/mg to about 3.0 ng·h/mL/mg; and AUC_(2.8-48h)of about 7.5 ng·h/mL/mg to about 15.0 ng·h/mL/mg.
 18. The pharmaceuticalcomposition of claim 17 wherein the AUC_(0-1hr) for acetaminophen isfrom about 1.25 ng·hr/mL/mg to about 3.25 ng·hr/mL/mg.
 19. Thepharmaceutical composition of claim 17 wherein the AUC_(0-2hr) foracetaminophen is from about 4.25 ng·hr/mL/mg to about 8.75 ng·hr/mL/mg.20. The pharmaceutical composition of claim wherein the AUC_(0-4hr) foracetaminophen is from about 10.0 ng·hr/mL/mg to about 20.0 ng·hr/mL/mg.21. The pharmaceutical composition of claim 17 wherein the AUC_(0-2hr)for oxycodone is from about 0.65 ng·hr/mL/mg to about 1.35 ng·hr/mL/mg.22. The pharmaceutical composition of claim 17 wherein the AUC_(0-4hr)for oxycodone is from about 2.0 ng·hr/mL/mg to about 4.0 ng·hr/mL/mg.23. A pharmaceutical composition as a solid oral dosage form for oraladministration useful in the treatment of pain and for reducing the riskof acetaminophen-induced hepatic damage, comprising: (a) at least oneimmediate release portion comprising about 125 mg to about 325 mg ofacetaminophen and about 1.5 mg to about 4.0 mg oxycodone or apharmaceutically acceptable salt thereof; and (b) at least one extendedrelease portion comprising about 125 mg to about 325 mg of acetaminophenand about 4.5 mg to about 6.5 mg oxycodone or salt thereof, and anextended release component; wherein the total amount of acetaminophen inthe composition is about 325 mg to about 650 mg, and the total amount ofoxycodone or salt in the composition is about 7.5 mg to about 10 mg; andwherein upon oral administration of two solid oral dosage forms of thecomposition in an amount of about 15 mg oxycodone or salt and about 650mg acetaminophen the composition maintains a therapeutic blood plasmaconcentration of oxycodone of at least about 5 ng/mL from about 0.75hours to about 10 hours after administration of the composition, andwherein at least about 90% of the acetaminophen is released from thecomposition by about 8 hours after administration of the compositionsuch that, by about 10 hours after administration of the composition,acetaminophen has a blood plasma concentration that is less than about30% of acetaminophen's maximum plasma concentration.
 24. Thepharmaceutical composition of claim 23, wherein upon oral administrationdepleted stores of hepatic glutathione are able to be substantiallyreplenished during the later part of a dosing internal when plasmaconcentrations of acetaminophen are reduced.
 25. The pharmaceuticalcomposition of claim 23, wherein the AUC_(Tmax-t) for acetaminophen isfrom about 20.0 ng·hr/mL/mg to about 40.0 ng·hr/mL/mg.
 26. Thepharmaceutical composition of claim 23, wherein the AUC_((1.7-48)) foracetaminophen is from about 25.0 ng·hr/mL/mg to about 75.0 ng·hr/mL/mg.27. The pharmaceutical composition of claim 1, wherein the compositionis administered to a subject as bilayer tablet.
 28. The pharmaceuticalcomposition of claim 27, wherein a single dose comprises two bilayertablets.
 29. The solid oral dosage form of claim 17, wherein the solidoral dosage form is a tablet of capsule.
 30. The solid oral dosage formof claim 23, wherein the solid oral dosage form is used in the treatmentof acute pain.